Angioedema, Acquired

Article Last Updated: May 21, 2007

AUTHOR AND EDITOR INFORMATION
Author: Warren R Heymann, MD, Head, Division of Dermatoloy, !rofessor, Department of
"nternal Medicine, University of Medicine and Dentistry of #e$ %ersey
&arren ' Heymann is a mem(er of the follo$in medical societies: American Academy of
Dermatoloy, American )ociety of Dermatopatholoy, and )ociety for "nvestiative
Dermatoloy
*oauthor+s,: Katheen M Ro!!y, MD, )taff !hysician, Department of Dermatoloy, #e$ -or.
Medical *ollee, Metropolitan Hospital
/ditors: Ro"ert A #ch$art%, MD, M&H, !rofessor and Head of Dermatoloy, !rofessor of
Medicine, !rofessor of !ediatrics, !rofessor of !atholoy, !rofessor of !reventive Medicine and
*ommunity Health, UMD#%0#e$ %ersey Medical )chool1 Michae ' We!, MD, Associate
!rofessor, Department of Dermatoloy, 2e3as 2ech University Health )ciences *enter1 &au
Kru!in!(i, MD, Director of Dermatoloy, !rofessor, Department of "nternal Medicine, 4letcher
Allen Health *are, University of 5ermont1 )atherine *uir(, MD, *linical Assistant !rofessor,
Department of Dermatoloy, 6ro$n University1 Wiiam D 'ame!, MD, !aul ' 7ross !rofessor
of Dermatoloy, University of !ennsylvania )chool of Medicine1 5ice0*hair, !roram Director,
Department of Dermatoloy, University of !ennsylvania Health )ystem
Author and Editor Di!co!ure
#ynonym! and reated (ey$ord!+ AA/, *ald$ell syndrome, ac8uired anioedema
INTRODU)TION
,ac(ground
Ac8uired anioedema +AA/, is characteri9ed (y painless, nonpruritic, nonpittin s$ellin of the
s.in that is classified into 2 forms: ac8uired anioedema type " +AA/0", and ac8uired
anioedema type "" +AA/0"",: AA/0" is associated $ith other diseases, most commonly 60cell
lymphoproliferative disorders: AA/0"" is an autoimmune process defined (y the presence of an
autoanti(ody directed aainst the *1 inhi(itor molecule +*10"#H,:
&atho-hy!ioogy
2he ene for *10"#H +SERPING1, has (een mapped to chromosome 11 +11812081;:1,: *10"#H
is a multifunctional serine protease inhi(itor that is normally present in hih concentrations in
plasma: "t is the only plasma inhi(itor of *1r and *1s, the activated proteases of the first
component of complement: "t is also the ma<or plasma inhi(itor of activated Haeman factor, the
first protease in the contact system: Additionally, *10"#H is one of the ma<or inhi(itors of
plasma .alli.rein, the contact system protease that cleaves .ininoen and releases (rady.inin:
!resuma(ly, uncontrolled activation of the contact system allo$s for release of .ininli.e
mediators, resultin in vascular permea(ility $ith edema of su(cutaneous and mucosal tissues:
Althouh the issue of $hich vasoactive peptide is ultimately responsi(le for these chanes
remain controversial, direct evidence supports the importance of (rady.inin in the clinical
manifestations of anioedema: =ther .inins may also (e pathoenic: 2he specific trier
responsi(le for inducin the release of these vasoactive peptides is unclear: 4actor >"" activation
+Haeman factor, may (e secondary to phospholipid release from damaed or apoptotic cells and
may (e important in the eneration of (rady.inin from endothelial activation: 2his hypothesis
encompasses the role of illness or tissue in<ury in the eneration of (rady.inin: 2he precise
pathophysioloy of AA/0" remains to (e defined: Diminished levels of *10"#H are due to its
increased cata(olism:
"n AA/0", the associated disorders +usually lymphoproliferative malinancies, produce
complement0activatin factors, idiotype?anti0idiotype anti(odies, or other immune comple3es
that destroy *10"#H function: #eoplastic lymphatic tissue has (een found to play an active role
in the consumption of *10"#H and the complement components of the classic path$ay: 2he most
commonly associated malinancy, 60cell lymphoma, has sho$n that anti0idiotypic anti(ody
attached to immunolo(ulin on the surface of 60cells causes *10"#H deficiency: "ncreased
consumption of *18 follo$ed (y *2 and *@ results in su(se8uent release of vasoactive peptides
that act on postcapillary venules:
"n AA/0"", a normal 10A0.d *10"#H molecule is synthesi9ed in ade8uate amounts, (ut, (ecause
of an un.no$n event, a su(population of 6 cells secretes autoanti(odies to the *10"#H
molecule: 2his autoanti(ody, $hich may (e any of the ma<or immunolo(ulin classes, (inds to
the reactive center of *10"#H: After (indin to *10"#H and alterin its structure, its reulatory
capacity is diminished or a(roated:
"n all reported cases of *10"#H deficiency caused (y an autoanti(ody, *10"#H circulates in the
(lood in a form that has (een cleaved (y taret proteases from its native molecule to a BA0.d
frament: 6ecause of the hiher affinity of the autoanti(ody for native *10"#H, the BA0.d
anti(ody?*10"#H comple3 dissociates, and the freed anti(ody can (ind to another native *10"#H
molecule, allo$in for the further depletion of *10"#H:
2he distinction (et$een AA/0" and AA/0"" may (e difficult to ma.e at times and it is imperative
to stress that overlap does occur: 4or instance, cases of monoclonal ammopathy of
undetermined sinificance + M7U), have sho$n the monoclonal immunolo(ulin itself to (e the
*10"#H anti(ody: 'eardin malinancies and?or other diseases associated $ith AA/0", it has
(een demonstrated that these patients may initially present $ith autoanti(odies to *10"#H, or
they may develop as the disease proresses:
Frequency
Internationa
AA/ is rare, $ith appro3imately 1A0 cases reported in the medical literature $orld$ide:
Mortaity.Mor"idity
Althouh mortality may occur (ecause of laryneal edema, it is more li.ely due to the
complications of the associated disorder:
Race
!resuma(ly, all races are affected:
#e/
Men and $omen may (e affected:
Age
2he onset of AA/ is most common after the fourth decade of life, $hereas the onset of
hereditary ac8uired anioedema +HA/, is in the second decade:
)0INI)A0

Hi!tory
A family history for hereditary anioedema is not o(tained, $hich distinuishes AA/
from HA/:

'eardin anioedema, symptoms are refera(le to ; prominent sites: su(cutaneous

tissues +e, face, hands, arms, les, enitals, (uttoc.s,1 a(dominal orans +e, stomach,
intestines, (ladder,, $hich may manifest as nausea, vomitin, and?or colic.y pain and
mimic a surical emerency1 and the upper air$ay +e, laryn3,, $hich may result in
laryneal edema:

=ccasionally, patients may e3perience heat and pain in the affected areas:

=ther symptoms may (e related to underlyin disorders, such as lymphoproliferative

malinancies or connective tissue disease:

&hy!ica
!hysical sins include overt, noninflammatory s$ellin of the s.in and mucous
mem(ranes:

Althouh urticaria does not usually occur, occasionally, erythema or mild urticarial
eruptions may precede the edema:

)au!e!
AA/0" is most fre8uently associated $ith 60cell lymphoproliferative disease: 2o date, only 2
reports of a 20cell lymphoma associated $ith AA/0" have (een documented: =ther disorders
have included multiple myeloma, chronic lymphocytic leu.emia, myelofi(rosis, &aldenstrCm
macrolo(ulinemia, non0Hod.in lymphoma, M7U), rectal carcinoma, essential
cryolo(ulinemia, erythrocyte sensiti9ation, livedo reticularis, cold urticaria, lupus anticoaulant,
and infection $ith Helicobacter pylori or Echinococcus granulosis. 6y definition, AA/0"" is not
associated $ith any specific disorder (ut rather (y the presence of the autoanti(ody directed
aainst *10"#H: Ho$ever, the occasional e3istence of features of (oth AA/0" and AA/0"" has
(een noted, most nota(ly $ith a M7U):
=ne case of AA/ $ith *10"#H deficiency state $as identified in association $ith liver
transplantation: 2he status of the liver donor $as un.no$n, (ut it is speculated that the donor
may have (een *10"#H deficient:
Another case of AA/ $as reported $ith acute upper air$ay anioedema in association $ith the
local anesthetic articaine:
DIFFERENTIA0#
)ection @ of 10

Anioedema, Hereditary
Dru /ruptions
Urticaria, Acute
Urticaria, *holineric
Urticaria, *hronic
Urticaria, *ontact )yndrome
Urticaria, Dermoraphism
Urticaria, )olar
Urticarial 5asculitis
Other &ro"em! to "e )on!idered
A*/ inhi(itorDinduced anioedema
/pisodic anioedema $ith anioedema
Leu.ocytoclastic vasculitis
Urticaria, cold
WORKU&
)ection A of 10
0a" #tudie!
AA/0" and AA/0""

o Lo$ *10"#H levels

o
o Lo$ *18 levels +e3cept 1 reported case,
o
o Lo$ *@ levels
o
o Lo$ *2 levels
o
AA/0"" 0 !ositive immuno(lot assay findins for BA0.d *10"#H cleavae product

Imaging #tudie!
A(dominal radioraphs may demonstrate features of ileus: =ther findins may (e
refera(le to an associated illness:

Other Te!t!
=ther la(oratory findins are related to associated illnesses:

Hi!toogic Finding!
Histoloic features include reticular dermal, su(cutaneous, or su(mucosal edema $ithout
infiltratin inflammatory cells: 5asodilation may (e seen:
TREATMENT
)ection E of 10

Medica )are
Dependin on the symptoms and the site of the anioedema, intensive support may (e
necessary, includin intravenous fluids:

&hen possi(le, the underlyin disorder should (e treated: 2he resolution of anioedema
has (een reported $ith the treatment of underlyin disease, althouh recurrences have
occurred despite appropriate treatment of the disorder:

"n AA/0", treatment of the associated lymphoproliferative process may result in

correction of the a(normality:

#urgica )are
"ntu(ation may (e necessary in cases of laryneal edema:
MEDI)ATION
)ection 7 of 10

"n AA/, therapy for acute attac.s may (e a(orted $ith *10"#H concentrates or, if unavaila(le,
fresh0fro9en plasma: Ho$ever, rapid cata(olism of *10"#H occurs in AA/, so hiher doses of
*10"#H plasma concentrate may (e needed:
Androens, such as dana9ol or stano9olol, may (e (eneficial in AA/0" (ut are of no value in
AA/0"": !rostate cancer and prenancy preclude the use of androens:
Antifi(rinolytics, such as epsilon0aminocaproic acid and trane3amic acid, have (een found to (e
more effective for lon0term prophyla3is in those $ith AA/:
"mmunosuppressive therapy directed to$ard decreasin autoanti(ody production may (e of
value in patients $ith AA/0"", $hich may (e accomplished (y the use of plasmapheresis $ith
cyclophosphamide:
A recent paper reported effective treatment of ; severe AA/ cases $ith a series of @ $ee.ly
in<ections $ith ritu3ima( +a chimeric monoclonal anti(ody to *D 20,: After treatment $ith
ritu3ima(, normali9ation of *10"#H and *@ levels and lon0term remission of anioedema
attac.s $as achieved:
#e$ medications are currently (ein studied for the treatment of AA/: =ne such treatment is a
synthetic .alli.rein inhi(itor +D>0FF,, $hich is thouht to (e a(le to stop the eneration of
(rady.inin (y inhi(itin .alli.rein activation: 2his dru allo$s for a decrease in the rate of *10
"#H cata(olism, allo$in for *10"#H concentrate to (e more effective:
=ther ne$ products in trial are enetically enineered *1 esterase inhi(itor and (rady.inin 62
receptor antaonist:
Drug )ategory+ Alkylating agents
)ome aents in this class have potent immunosuppressive activity:
Drug Name *yclophosphamide +*yto3an, #eosar,
De!cri-tion
*hemically related to nitroen mustards: As an
al.ylatin aent, the mechanism of action of the
active meta(olites may involve cross0lin.in of
D#A, $hich may interfere $ith ro$th of normal
and neoplastic cells:
Adut Do!e A0007A0 m?m
2
&ediatric Do!e Administer as in adults
)ontraindication!
Documented hypersensitivity1 severely depressed
(one marro$ function
Interaction!
Allopurinol may increase ris. of (leedin or
infection and enhance myelosuppressive effects1
may potentiate do3oru(icin0induced cardioto3icity1
may reduce dio3in serum levels and antimicro(ial
effects of 8uinolones1 chloramphenicol may
increase half0life $hile decreasin meta(olite
concentrations1 may increase effect of
anticoaulants1 coadministration $ith hih doses
of pheno(ar(ital may increase rate of meta(olism
and leu.openic activity1 thia9ide diuretics may
prolon cyclophosphamide0induced leu.openia
and neuromuscular (loc.ade (y inhi(itin
cholinesterase activity
&regnancy D 0 Unsafe in prenancy
&recaution!
'eularly e3amine hematoloic profile
+particularly neutrophils and platelets, to monitor
for hematopoietic suppression1 reularly e3amine
urine for '6*s, $hich may precede hemorrhaic
cystitis1 hematoloic myelosuppression, primarily
leu.openia, is most common adverse effect1
throm(ocytopenia and anemia occur less
fre8uently1 astrointestinal adverse effects include
anore3ia, nausea, emesis, and stomatitis1 uroloic
adverse effects include dysuria, urency,
hematuria, (ladder fi(rosis, and necrosis1 death
from hemorrhaic cystitis has occurred1 encourae
e3cessive fluid inta.e1 interferes $ith ooenesis
and spermatoenesis1 may cause irreversi(le
sterility in (oth se3es
Drug )ategory+ Antifibrinolytic agents
Act throuh the inhi(ition of plasmin:
Drug Name Aminocaproic acid +Amicar,
De!cri-tion
Lysine analo that inhi(its fi(rinolysis via
inhi(ition of plasminoen activator su(stances1 to
a lesser deree, throuh antiplasmin activity:
&idely distri(uted: Half0life is 102 h: !ea. effect
occurs $ithin 2 h: Hepatic meta(olism is minimal:
*an (e used !=?"5:
Adut Do!e
F 8@h "5, then 1E ?d in acute attac.s
E010 ?d != maintenance
&ediatric Do!e
F010 ?d !=
#ot recommended in ne$(orns
)ontraindication!
Documented hypersensitivity1 evidence of active
intravascular clottin process1 coadministration
$ith factor "> comple3 concentrates or anti0
inhi(itor coaulant comple3es1 in<ection in
premature neonates +in<ecta(le product contains
(en9yl alcohol,
Interaction!
*oadministration $ith estroens may cause
increase in clottin factors, leadin to a
hypercoaula(le state1 coadministration $ith
tretinoin my increase ris. of (oth venous and
arterial throm(osis
&regnancy
* 0 )afety for use durin prenancy has not (een
esta(lished:
&recaution!
Do not administer unless a definite dianosis of
hyperfi(rinolysis has (een made1 caution in
cardiac, hepatic or renal disease1 (ecause
aminocaproic acid can (e fatal in patients $ith
D"*, important to differentiate (et$een
hyperfi(rinolysis and D"*1 throm(i that form
durin treatment are not lysed and effectiveness is
uncertain1 associated adverse effects are postural
hypotension, throm(osis, and muscular pain and
$ea.ness1 monitor *G levels1 caution in patients
$ith upper urinary tract (leedin1 caution $ith
rapid infusions1 do not administer $ith factor ">
comple3 concentrates or anti0inhi(itor coaulant
comple3es1 adverse effects include
(radyarrhythmia, dru0induced myopathy, and
hypotension
Drug Name 2rane3amic acid +*y.lo.apron,
De!cri-tion
Alternative to aminocaproic acid: "nhi(its
fi(rinolysis (y displacin plasminoen from fi(rin:
Adut Do!e
Up to F !=?"5 for acute attac.s
102 != for maintenance
;0@:A !=?"5 8d divided tid?8id pc1 continue for
period lon enouh for at least ;0@ attac.s to have
normally occurred
&ediatric Do!e
1202A m?.?dose +not to e3ceed 1:A , != tid?8id
for acute attac. or as prophyla3is for A d
)ontraindication!
Documented hypersensitivity1 active intravascular
clottin process1 ac8uired defective color vision1
su(arachnoid hemorrhae
Interaction! #ot esta(lished
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution!
*aution in renal impairment1 adverse effects are
not common (ut include headaches, nausea,
a(dominal pain, and diarrhea1 evidence of tumor
formation in retina and liver found in e3perimental
animal models after lon0term use1 althouh no
evidence has supported these findins in humans,
annual funduscopic e3aminations and L42
monitorin recommended 8Emo if on lon0term
therapy1 perform (aseline ophthalmoloic
e3amination (efore initiatin therapy1 caution in
history of throm(oem(olic disease and
disseminated intravascular coaulation
Drug )ategory+ Antigonadotropic agents
2hese aents have immunosuppressive properties:
Drug Name Dana9ol +Danocrine,
De!cri-tion
"ncreases levels of *@ component of complement
and prevents attac.s associated $ith anioedema:
Adut Do!e
200 m != (id?tid initially1 if efficacious, taper
dose (y A0H over follo$in 20; mo
&ediatric Do!e #ot esta(lished
)ontraindication! Documented hypersensitivity1 sei9ure disorders1
renal or hepatic insufficiency1 cardiac disease1
(reastfeedin1 conditions influenced (y edema1
undianosed enital (leedin1 porphyria1
carcinoma of the (reast
Interaction!
Decreases insulin re8uirements and increases
effects of anticoaulants1 concomitant
administration $ith car(ama9epine may result in
to3icity1 coadministration $ith HM70*oA
reductase inhi(itors may increase ris. for
rha(domyolysis1 cyclosporine and?or tacrolimus
to3icity may increase if coadministered $ith
dana9ol1 concomitant use $ith car(ama9epine may
increase ris. of car(ama9epine to3icity1
concomitant administration $ith cyclosporine or
tacrolimus and ana(olic steroids may result in
increased cyclosporine or tacrolimus (lood levels
and to3icity1 may result in increased lovastatin
plasma concentrations $hen administered
concurrently +use only if potential (enefit <ustifies
potential ris. of developin
myopathy?rha(domyolysis,
&regnancy > 0 *ontraindicated in prenancy
&recaution!
*aution in renal, hepatic, or cardiac insufficiency
and sei9ure disorders1 peliosis hepatitis and (enin
hepatic adenoma have (een o(served $ith lon0
term therapy1 throm(oem(olic events and
pseudotumor cere(ri reported1 androenli.e
effects, includin $eiht ain, acne, hirsutism,
edema, hair loss, voice chane, and menstrual
distur(ances, occur1 temporary alteration of
lipoproteins may occur1 consider the impact on the
ris. of atherosclerosis and coronary artery disease1
serum total testosterone values may (e falsely
elevated if radioimmunoassay done to measure
testosterone in $omen ta.in dana9ol
Drug Name )tano9olol +&instrol,
De!cri-tion
)ynthetic androen $ith immunosuppressive
properties: "ncreases levels of *1 esterase inhi(itor
and *@ component of the complement:
Adut Do!e
2 m != tid and reduce to maintenance dose of 2
m?d or 2 m 8od after 10; mo
&ediatric Do!e
IE years: 1 m?d !=
E012 years: 2 m?d !=
J12 years: Administer as in adults
)ontraindication! Documented hypersensitivity1 nephrosis1 (reast or
prostate cancer
Interaction!
"ncreases hypoprothrom(inemic effects of oral
anticoaulants and hypolycemic effects of insulin
and sulfonylureas
&regnancy > 0 *ontraindicated in prenancy
&recaution!
May cause peliosis hepatitis, liver cell tumors, and
(lood lipid chanes $ith increased ris. of
arteriosclerosis1 caution in cardiac, renal, or
hepatic disease or epilepsy1 adverse effects include
cholestatic <aundice syndrome and?or hepatic
necrosis +causin death,1 may cause premature
epiphyseal closure in children1 caution in dia(etic
patients and pediatric patients1 may cause
suppression of clottin factors "", 5, 5"", and > and
an increase in prothrom(in time
FO00OW1U&
)ection F of 10
Authors and /ditors
"ntroduction
*linical
Differentials
&or.up
2reatment
Medication
4ollo$0up
Miscellaneous
'eferences
&rogno!i!
2he pronosis is varia(le, (ut it predominantly depends on control of the underlyin
disorder:

*ompared $ith the eneral population, patients $ith AA/ have a hiher incidence of 60
cell malinancies:

!atients $ith AA/ and a concurrent dianosis of M7U) do not have an increased ris. for
proression to malinancy compared $ith patients $ith a sole dianosis of M7U):

&atient Education
4or e3cellent patient education resources, visit eMedicineKs Allery *enter and ).in,
Hair, and #ails *enter: Also, see eMedicineKs patient education article Hives and
Anioedema:

MI#)E00ANEOU#
)ection B of 10

#-ecia )oncern!
2rane3amic acid may (e used durin prenancy:

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)ection 10 of 10
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1F: MMedlineN:
Angioedema, Acquired excerpt
Article Last Updated: May 21, 2007
Angioedema, Hereditary
Article Last Updated: May 1F, 2007
AUTHOR AND EDITOR INFORMATION
)ection 1 of B

Author: Warren R Heymann, MD, Head, Division of Dermatoloy, !rofessor, Department of

"nternal Medicine, University of Medicine and Dentistry of #e$ %ersey
&arren ' Heymann is a mem(er of the follo$in medical societies: American Academy of
Dermatoloy, American )ociety of Dermatopatholoy, and )ociety for "nvestiative
Dermatoloy
*oauthor+s,: Katheen M Ro!!y, MD, )taff !hysician, Department of Dermatoloy, #e$ -or.
Medical *ollee, Metropolitan Hospital
/ditors: Ro"ert A #ch$art%, MD, M&H, !rofessor and Head of Dermatoloy, !rofessor of
Medicine, !rofessor of !ediatrics, !rofessor of !atholoy, !rofessor of !reventive Medicine and
*ommunity Health, UMD#%0#e$ %ersey Medical )chool1 Michae ' We!, MD, Associate
!rofessor, Department of Dermatoloy, 2e3as 2ech University Health )ciences *enter1 &au
Kru!in!(i, MD, Director of Dermatoloy, !rofessor, Department of "nternal Medicine, 4letcher
Allen Health *are, University of 5ermont1 )atherine *uir(, MD, *linical Assistant !rofessor,
Department of Dermatoloy, 6ro$n University1 Wiiam D 'ame!, MD, !aul ' 7ross !rofessor
of Dermatoloy, University of !ennsylvania )chool of Medicine1 5ice0*hair, !roram Director,
Department of Dermatoloy, University of !ennsylvania Health )ystem
Author and Editor Di!co!ure
#ynonym! and reated (ey$ord!+ hereditary anioedema, HA/, *10"#H, *1 inhi(itor,
s$ellin of the s.in
INTRODU)TION
)ection 2 of B

,ac(ground
Hereditary anioedema +HA/, is an autosomal dominant disorder of *1 inhi(itor +*10"#H,
deficiency manifested (y painless, nonpruritic, nonpittin s$ellin of the s.in: 2ype " HA/ is
defined (y lo$ plasma levels of a normal *10"#H protein: 2ype "" HA/ is characteri9ed (y the
presence of normal or elevated levels of a dysfunctional *10"#H: 2ype """ HA/ has (een
recently identified as an estroen0dependent inherited form of anioedema occurrin mainly in
$omen $ith normal functional and 8uantitative levels of *10"#H:
&atho-hy!ioogy
2he ene for *10"#H +SERPING1, has (een mapped to 11812081;:1: *10"#H is a
multifunctional serine protease inhi(itor that is normally present in hih concentrations in
plasma: "t is the only .no$n plasma inhi(itor of *1r and *1s, the activated proteases of the first
component of complement: "t is also the ma<or plasma inhi(itor of activated factor >""
+Haeman factor,, the first protease in the contact system: Additionally, *10"#H is one of the
ma<or inhi(itors of plasma .alli.rein, the contact system protease that cleaves .ininoen and
releases (rady.inin:
!resuma(ly, uncontrolled activation of the contact system allo$s for the release of .ininli.e
mediators, resultin in edema of su(cutaneous or su(mucosal tissues: Althouh the issue of
$hich vasoactive peptide is ultimately responsi(le for these chanes remains controversial, direct
evidence supports the importance of (rady.inin in the clinical manifestations of anioedema:
=ther .inins may also (e pathoenic: 2he incitin factor responsi(le for inducin the release of
these vasoactive peptides is unclear: 4actor >"" activation may (e secondary to a enetic
mutation or phospholipid release from damaed or apoptotic cells and may (e important in the
eneration of (rady.inin from endothelial activation: 2his hypothesis encompasses the role of
illness or tissue in<ury in the eneration of (rady.inin:
HA/ is due to mutations $ithin the *10"#H ene +C1NH, and is transmitted as an autosomal
dominant trait: Appro3imately 1A0 different enetic mutations have (een descri(ed in HA/, and
a spontaneous mutation rate of 2AH has (een reported: 2he 2 variants of HA/ related to *10"#H
function are type " +FAH, and type "" +1AH,:
2ype " HA/ is characteri9ed (y lo$ antienic and functional plasma levels of a normal *10"#H
protein: 2ype "" HA/ is characteri9ed (y the presence of normal or elevated antienic levels of a
dysfunctional mutant protein toether $ith reduced levels of the functional protein: *10"#H
deficiency allo$s autoactivation of *1, $ith consumption of *@ and *2: "n type """ HA/, the
*10"#H protein is (oth 8ualitatively and functionally normal: 2he e3act mechanism of action
responsi(le for the lin. (et$een estroen and anioedema is unclear: =ne theory suests that
estroen plays a role in up0reulatin the production of (rady.inin and decreasin its
deradation (y aniotensin0convertin en9yme +A*/,: A more recent theory suests a mutation
in factor >"" that allo$s for the inappropriate activation of the .inin cascade:
Frequency
Internationa
HA/ is estimated to occur in 1 in A0,00001A0,000 individuals:
Mortaity.Mor"idity
Mortality rates are estimated at 1A0;;H, resultin from laryneal edema and asphy3iation:
Race
!ersons of any race can (e affected, $ith no reported (ias in different ethnic roups:
#e/
Men and $omen are e8ually affected for HA/ types " and "": HA/ type """ $as initially thouht
to occur only in $omen, (ut recent family studies have descri(ed males $ith HA/ and normal
*1 inhi(itor levels: Althouh a fe$ male cases have (een cited in the literature, HA/ type """ is
still thouht to predominantly affect $omen:
Age
*10"#H deficiency is present at (irth, althouh only a fe$ patients have (een reported $ith
perinatal anioedema: )ymptoms usually (ecome apparent in the first or second decade of life:
Appro3imately @0H of people $ith HA/ e3perience their first episode (efore ae A years, and
7AH present (efore ae 1A years: !atients typically e3perience minor s$ellin in childhood that
may o unnoticed, $ith increased severity around pu(erty: HA/ is a lifelon affliction, althouh
some report decreased symptoms $ith ae: 4ive percent of adults $ith HA/ are asymptomatic
$hile carryin the C1NH mutation, and they are only identified after their children are found to
(e symptomatic:
)0INI)A0
)ection ; of B

Hi!tory
A family history of HA/ is typically o(tained, althouh spontaneous mutations may
occur:

)ymptoms are refera(le to ; prominent sites: su(cutaneous tissues +face, hands, arms,
les, enitals, and (uttoc.s,1 a(dominal orans +stomach, intestines, (ladder, and
.idneys,, $hich may manifest as vomitin, diarrhea, or paro3ysmal colic.y pain and
mimic a surical emerency1 and the upper air$ay +laryn3, and tonue, $hich may result
in laryneal edema and upper air$ay o(struction:

Attac.s usually occur at a sinle site, (ut simultaneous involvement of su(cutaneous

tissue, viscera, and the laryn3 is not uncommon: #onpittin cutaneous s$ellin is the
most commonly reported symptom, and it mainly affects the e3tremities, the enitalia,
and the face: Acute a(dominal pain, nausea, and vomitin are the dominant symptoms in
2AH of patients $ith HA/ and are rarely seen in people $ith other forms of anioedema:
2he lifetime incidence of a laryneal attac. is estimated at 70H:

Mucosal edema of the (ladder or urethra can result in urinary retention, stammerin,
pain, or anuria:

/pisodes of severe headaches, visual distur(ances +e, (lurred vision, diplopia,, and
ata3ia have (een reported:

*ases of painful muscle s$ellin and unilateral hip or shoulder involvement have also
(een cited:

Attac.s may (e preceded several hours in advance (y sudden mood chanes, an3iety,
sensory chanes, or e3haustion:

!atients often report episodes of s$ellin $orsenin over a period of 1202@ hours, usually
$ith resolution $ithin 72 hours: )ymptoms can persist for up to A days, $ith miration of
s$ellin to different sites: 2he edema is usually unresponsive to antihistamines: Attac.s
are usually periodic and are commonly follo$ed (y $ee.s of remission:

!ediatric episodes are usually less fre8uent and commonly manifest as a(dominal
involvement:
&hy!ica
!hysical sins include overt, noninflammatory s$ellin of the s.in and mucous
mem(ranes: 2ypical involvement includes the face, hands, arms, les, enitalia, and
(uttoc.s, althouh the edema can locali9e su(cutaneously at any site: "n some patients
$ith severe edema, tension vesicles or (ullae may develop:

"n appro3imately 2AH of patients, erythema may precede the occurrence of edema: An
estimated ;00A0H of patients $ith HA/ reportedly have erythema marinatum precedin
or accompanyin the attac.s: Urticaria is not usually associated $ith HA/:

A(dominal e3amination may reveal sins consistent $ith acute a(domen or a(dominal
o(struction: Ascites is often present $ith an a(dominal attac. associated $ith
anioedema:

Mucosal involvement $ith lossal, pharyneal, or laryneal edema may cause respiratory
o(struction and sins of distress:

Additional rare physical findins that have (een reported are pleuritic symptoms $ith
pleural effusions, sei9ures and hemiparesis secondary to cere(ral edema, and (ladder
edema:
)au!e!
!recipitatin factors of attac.s may include trauma +especially dental trauma,, an3iety,
menstruation, infection, e3ercise, alcohol consumption, and stress: Medications +e,
estroen, A*/ inhi(itors, aniotensin "" type 1 receptor antaonists, have also (een
sho$n to induce attac.s:

Durin prenancy, symptoms may increase or decrease for HA/ types " and "": "n HA/
type """, studies have reported first episodes or recurrences associated $ith estroen0
containin oral contraceptives, estroen replacement therapy, or prenancy:

As many as 2H of patients $ith HA/ may have systemic lupus erythematosus: Less
commonly, other autoimmune disorders, such as lomerulonephritis, rheumatoid arthritis,
thyroiditis, )<Cren syndrome, and pernicious anemia, may (e associated $ith HA/:

2hose HA/ patients infected $ith Helicobacter pylori have (een found to (e more
symptomatic than those $ho are not infected:
DIFFERENTIA0#
)ection @ of B
Authors and /ditors
"ntroduction
*linical
Differentials
&or.up
2reatment
Medication
4ollo$0up
'eferences
Anioedema, Ac8uired
Dru /ruptions
Urticaria, Acute
Urticaria, *holineric
Urticaria, *hronic
Urticaria, *ontact )yndrome
Urticaria, Dermoraphism
Urticaria, !ressure
Urticaria, )olar
Urticarial 5asculitis
Other &ro"em! to "e )on!idered
A*/ inhi(itorDinduced anioedema
/pisodic anioedema $ith eosinophilia
5i(ratory0 or pressure0induced anioedema
WORKU&
)ection A of B
0a" #tudie!
'outine la(oratory test results are usually normal, althouh a leu.ocytosis may occur $ith
astrointestinal episodes: /levation of the hematocrit value may (e o(served (ecause of
intravascular fluid loss:
2ype " HA/
o *10"#H level is lo$:
o
o *@ and *2 levels are lo$:
o
o *18 level is normal:

2ype "" HA/

o *10"#H level is normal or elevated (ut dysfunctional:
o
o *@ and *2 levels are lo$:
o
o *18 level is normal:

2ype """ HA/

o *10"#H level is normal:
o
o *10"#H functional assay is normal:
o
o *@ level may (e normal:
Imaging #tudie!
A(dominal radioraphs may demonstrate features of ileus:

A(dominal ultrasonoraphy or computed tomoraphy may sho$ edematous thic.enin

of the intestinal $all, a fluid layer around the (o$el, and lare amounts of free peritoneal
fluid:

*hest radioraphs may demonstrate pleural effusions:

Hi!toogic Finding!
Histoloic features include edema in the reticular dermis or su(cutaneous or su(mucosal edema
$ithout infiltratin inflammatory cells: 5asodilation may (e present:
TREATMENT
)ection E of B
Authors and /ditors
"ntroduction
*linical
Differentials
&or.up
2reatment
Medication
4ollo$0up
'eferences
Medica )are
Dependin on the symptoms and the sites of the anioedema, intensive support may (e
necessary, includin intravenous fluids: "n cases of serious laryneal edema causin
respiratory o(struction, intu(ation or tracheostomy should (e performed: "n HA/ types "
and "", the treatment of choice in acute attac.s consists of replacement $ith commercially
availa(le *10"#H concentrates or, if unavaila(le, fresh0fro9en plasma: "n HA/ type """,
infusion of *10"#H has proven to (e ineffective:

!rophylactic treatment is instituted if patients are afflicted $ith fre8uent and?or severe
episodes:
o Dana9ol or stano9olol may (e used at doses that prevent attac.s1 normali9in the
levels of *10"#H is not necessary: 2he most sinificant complication of lon0term
use may (e arterial hypertension: 2he 170alpha0al.ylated androens rarely cause
hepatoto3icity and liver tumors, (ut they should (e used at the lo$est effective
dosae: 'eular monitorin of liver function test results, lipid levels, and liver
ultrasonoraphy findins is recommended:
o
o Althouh virili9ation may (e an issue $ith $omen, .eepin to the lo$est possi(le
dose usually o(viates this concern:
o
o *ontraindications to the use of androens include prostate cancer, prenancy,
childhood, and (reastfeedin:
o
o Antifi(rinolytic aents such as epsilon0aminocaproic acid or trane3amic acid can
also (e used for prophyla3is, althouh they have not (een found to (e as effective
as the androenic aents: 2hese aents are the option for prenant $omen:
o
o )hort0term prophyla3is for surical procedures, especially dental $or., is
necessary: *10"#H infusions can (e iven 2@ hours (efore the procedure or <ust
prior to it: Alternatives, such as antifi(rinolytics or androens, can (e used, and
they should (e started A days (efore the procedure and continued for 2 days
after$ards:
/radication of the underlyin cause of the attac., such as H pylori or another infectious
aent, may lead to resolution of symptoms: *areful attention should (e iven to
medications (ein ta.en (y the patient that may have contri(uted to an attac., such as
contraceptives, hormone replacement therapy, or A*/ inhi(itors:

*linical trials are currently under$ay for several ne$ therapies for acute attac.s of
anioedema: 2he ne$ therapies, such as recom(inant human *10"#H, recom(inant
.alli.rein inhi(itor +D>0FF,, and (rady.inin02 receptor antaonist +icati(ant,, may offer
safer and more effective treatment options: )everal protease inhi(itors have (een found to
have functional overlap $ith *10"#H +e, antithrom(in """, (eta0macrolo(ulin, alpha10
antitrypsin, and may (e therapeutic options in the future:
#urgica )are
"ntu(ation may (e necessary in cases complicated (y laryneal edema:
MEDI)ATION
)ection 7 of B

2he oals of pharmacotherapy are to reduce mor(idity and to prevent complications:

Drug )ategory+ Antigonadotropic agents
2hese aents may (e used at doses that prevent attac.s:
Drug Name Dana9ol +Danocrine,
De!cri-tion
"ncreases levels of *@ component of complement
and reduces attac.s associated $ith anioedema: "n
HA/, dana9ol increases level of deficient *1
esterase inhi(itor:
Adut Do!e
)hort0term prophyla3is: 1000E00 m?d !=
Lon term prophyla3is: 200 m != tid1 taper to
lo$est effective dose
&ediatric Do!e #ot esta(lished
)ontraindication!
Documented hypersensitivity1 sei9ure disorders1
renal or hepatic insufficiency1 cardiac disease1
(reastfeedin1 conditions influenced (y edema1
undianosed enital (leedin1 porphyria
Interaction!
Decreases insulin re8uirements and increases
effects of anticoaulants1 may increase
car(ama9epine levels
&regnancy > 0 *ontraindicated in prenancy
&recaution!
*aution in renal, hepatic, or cardiac insufficiency
and sei9ure disorders1 peliosis hepatitis and (enin
hepatic adenoma have (een o(served $ith lon0
term therapy +J10 y,1 throm(oem(olic events and
pseudotumor cere(ri reported1 androenli.e
effects, includin $eiht ain, acne, hirsutism,
edema, hair loss, voice chanes, and menstrual
distur(ances, occur
Drug Name )tano9olol +&instrol,
De!cri-tion
)ynthetic androen $ith immunosuppressive
properties: "ncreases levels of *1 esterase inhi(itor
and *@ component of complement:
Adut Do!e
2 m != tid and reduce to maintenance dose of 2
m?d != or 2 m != 8od after 10; mo
&ediatric Do!e
IE years: 1 m?d !=
E012 years: 2 m?d !=
J12 years: Administer as in adults
)ontraindication!
Documented hypersensitivity1 nephrosis1 (reast or
prostate cancer
Interaction!
"ncreases hypoprothrom(inemic effects of oral
anticoaulants and hypolycemic effects of insulin
and sulfonylureas
&regnancy > 0 *ontraindicated in prenancy
&recaution! May cause peliosis hepatitis, liver cell tumors, and
(lood lipid chanes $ith increased ris. of
arteriosclerosis1 caution in cardiac, renal, or
hepatic disease or epilepsy1 may increase !21
phallic or clitoral enlarement, hirsutism,
ynecomastia, acne, edema, nausea, vomitin, and
diarrhea may occur
Drug )ategory+ Antifibrinolytic agents
Act throuh the inhi(ition of plasmin:
Drug Name /psilon0aminocaproic acid +Amicar,
De!cri-tion
Lysine analo that inhi(its fi(rinolysis via
inhi(ition of plasminoen activator su(stances and,
to a lesser deree, throuh antiplasmin activity:
&idely distri(uted: Half0life is 102 h: !ea. effect
occurs $ithin 2 h: Hepatic meta(olism is minimal:
*an (e used !=?"5:
Adut Do!e
Acute attac.: F 8@h "5, then 1E ?d
Maintenance: E010 ?d !=
&ediatric Do!e
F010 ?d !=
#ot recommended in ne$(orns
)ontraindication!
Documented hypersensitivity1 evidence of active
intravascular clottin process1 coadministration
$ith factor "> comple3 concentrates or anti0
inhi(itor coaulant comple3es
Interaction!
*oadministration $ith estroens may cause
increase in clottin factors, leadin to a
hypercoaula(le state
&regnancy
* 0 )afety for use durin prenancy has not (een
esta(lished:
&recaution! Do not administer unless a definite dianosis of
hyperfi(rinolysis has (een made1 caution in
cardiac, hepatic, or renal disease1 (ecause
aminocaproic acid can (e fatal in patients $ith
D"* +important to differentiate (et$een
hyperfi(rinolysis and D"*,1 throm(i that form
durin treatment are not lysed and effectiveness is
uncertain1 associated adverse effects are postural
hypotension, throm(osis, and muscular pain and
$ea.ness1 monitor *G levels1 caution in patients
$ith upper urinary tract (leedin1 caution $ith
rapid infusions1 do not administer $ith factor ">
comple3 concentrates or anti0inhi(itor coaulant
comple3es
Drug Name 2rane3amic acid +*y.lo.apron,
De!cri-tion
Alternative to aminocaproic acid: "nhi(its
fi(rinolysis (y displacin plasminoen from fi(rin:
Adut Do!e
Acute attac.: Up to F !=?"5
Maintenance: 102 !=
&ediatric Do!e
1202A m?.?dose +not to e3ceed 1:A , != tid?8id
recommended
)ontraindication! Documented hypersensitivity
Interaction! #ot esta(lished
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution!
*aution in renal impairment1 adverse effects are
not common (ut include headaches, nausea,
a(dominal pain, and diarrhea1 evidence of tumor
formation in retina and liver found in e3perimental
animal models after lon0term use1 althouh no
evidence has supported these findins in humans,
annual funduscopic e3aminations and L42
monitorin recommended 8Emo if on lon0term
therapy1 perform (aseline ophthalmoloic
e3amination (efore initiatin therapy
FO00OW1U&
&rogno!i!
!atients $ith an early onset of attac.s have a $orse pronosis than those $ith a late onset
of attac.s:

&ith appropriate use of prophylactic therapy, the pronosis for patients $ith HA/ is
e3cellent:
&atient Education
4or more information, visit the United )tates Hereditary Anioedema Association:

4or e3cellent patient education resources, visit eMedicineKs Allery *enter and ).in,
Hair, and #ails *enter: "n addition, see eMedicineKs patient education article Hives and
Anioedema:
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Angioedema, Hereditary excerpt
Article Last Updated: May 18, 2007
Drug Eru-tion!
Article Last Updated: Mar 2F, 2007
AUTHOR AND EDITOR INFORMATION
)ection 1 of 11

Author: 'onathan E ,ume, MD, "nstructor in *linical Dermatoloy, *olum(ia University

*ollee of !hysicians and )ureons1 *onsultin )taff, &est$ood Dermatoloy and
Dermatoloic )urery 7roup, !A
%onathan / 6lume is a mem(er of the follo$in medical societies: Alpha =mea Alpha,
American Academy of Dermatoloy, American *ontact Dermatitis )ociety, American Medical
Association, American )ociety for Dermatoloic )urery, "nternational )ociety of Dermatoloy,
and #ational !soriasis 4oundation
*oauthor+s,: Thoma! N Hem, MD, *linical Associate !rofessor, Departments of Dermatoloy
and !atholoy, )tate University of #e$ -or. at 6uffalo1 Director, 6uffalo Medical 7roup
Dermatopatholoy La(oratory1 Michee Ehrich, MD, 4ello$ for the American Academy of
*osmetic )urery, )taff !hysician, Department of Dermatoloy, La %olla )paMD1 )hare!
)ami!a, MD, Head of *linical Dermatoloy, 5ice0*hair, Department of Dermatoloy,
*leveland *linic 4oundation
/ditors: Nei #hear, MD, !rofessor and *hief of Dermatoloy, !rofessor of Medicine, !ediatrics
and !harmacoloy, University of 2oronto 4aculty of Medicine1 Head of Dermatoloy,
)unny(roo. &omenKs *ollee Health )ciences *enter and &omenKs *ollee Hospital, *anada1
Richard & 2in!on, MD, Assistant *linical !rofessor, Department of Dermatoloy, 2e3as 2ech
University )chool of Medicine1 *onsultin )taff, Mountain 5ie$ Dermatoloy, !A1 'e33rey &
)aen, MD, !rofessor of Medicine, *hief, Division of Dermatoloy, University of Louisville
)chool of Medicine1 )atherine *uir(, MD, *linical Assistant !rofessor, Department of
Dermatoloy, 6ro$n University1 Dir( M E!ton, MD, Director, Department of Dermatoloy,
7eisiner Medical *enter
Author and Editor Di!co!ure
#ynonym! and reated (ey$ord!+ adverse cutaneous dru reactions, cutaneous reaction to
drus, dru0induced cutaneous reactions, mucocutaneous dru reactions, dermatoses, dermatosis,
cutaneous eruptions, cutaneous dru reactions, adverse dru reactions, dru allery, fi3ed dru
reactions, medication adverse effects, medication side effects, adverse effects, side effects,
medication allery
INTRODU)TION
)ection 2 of 11
,ac(ground
Dru eruptions can mimic a $ide rane of dermatoses: 2he morpholoies are myriad and include
mor(illiform +most common, see Media file 1,, urticarial, papulos8uamous, pustular, and
(ullous: Medications can also cause pruritus and dysesthesia $ithout an o(vious eruption:
A dru0induced reaction should (e considered in any patient $ho is ta.in medications and $ho
suddenly develops a symmetric cutaneous eruption: Medications that are .no$n for causin
cutaneous reactions include antimicro(ial aents, nonsteroidal anti0inflammatory drus
+#)A"Ds,, cyto.ines, chemotherapeutic aents, anticonvulsants, and psychotropic aents:
!rompt identification and $ithdra$al of the offendin aent may help limit the to3ic effects
associated $ith the dru: 2he decision to discontinue a potentially vital dru often presents a
dilemma:
&atho-hy!ioogy
Dru eruptions may (e divided into immunoloically and nonimmunoloically mediated
reactions:
Immunoogicay mediated reaction!
*oom(s and 7ell proposed @ types of immunoloically mediated reactions, as follo$s:
2ype " is immunolo(ulin / +"/,Ddependent reactions, $hich result in urticaria,
anioedema, and anaphyla3is +see Media file 1A,:
2ype "" is cytoto3ic reactions, $hich result in hemolysis and purpura +see Media file B,:
2ype """ is immune comple3 reactions, $hich result in vasculitis, serum sic.ness, and
urticaria:
2ype "5 is delayed0type reactions $ith cell0mediated hypersensitivity, $hich result in
contact dermatitis, e3anthematous reactions, and photoalleric reactions:
"nsulin and other proteins are associated $ith type " reactions: !enicillin, cephalosporins,
sulfonamides, and rifampin are .no$n to cause type "" reactions: Ruinine, salicylates,
chlorproma9ine, and sulfonamides can cause type """ reactions: 2ype "5 reactions, the most
common mechanism of dru eruptions, are often encountered in cases of contact hypersensitivity
to topical medications, such as neomycin: )ulfonamides are most fre8uently associated $ith
to3ic epidermal necrolysis +2/#,:
Althouh most dru eruptions are type "5 hypersensitivity reactions, only a minority are "/0
dependent: 2hat is, anti(odies can (e demonstrated in less than AH of cutaneous dru reactions:
2ype "5 cell0mediated reactions are not dose dependent, they usually (ein 7020 days after the
medication is started, they may involve (lood or tissue eosinophilia, and they may recur if drus
chemically related to the causative aent are administered:
Nonimmunoogicay mediated reaction!
#onimmunoloically mediated reactions may (e classified accordin to the follo$in features:
accumulation, adverse effects, direct release of mast cell mediators, idiosyncratic reactions,
intolerance, %arisch0Her3heimer phenomenon, overdosae, or phototo3ic dermatitis: +)ymptoms
of %arisch0Her3heimer reactions disappear $ith continued therapy: Dru therapy should (e
continued until the infection is fully eradicated:,
An e3ample of accumulation is aryria +(lue0ray discoloration of s.in and nails, o(served $ith
use of silver nitrate nasal sprays:
Adverse effects are normal (ut un$anted effects of a dru: 4or e3ample, antimeta(olite
chemotherapeutic aents, such as cyclophosphamide, are associated $ith hair loss:
2he direct release of mast cell mediators is a dose0dependent phenomenon that does not involve
anti(odies: 4or e3ample, aspirin and other #)A"Ds cause a shift in leu.otriene production,
$hich triers the release of histamine and other mast0cell mediators: 'adioraphic contrast
material, alcohol, cyto.ines, opiates, cimetidine, 8uinine, hydrala9ine, atropine, vancomycin, and
tu(ocurarine also may cause release of mast0cell mediators:
"diosyncratic reactions are unpredicta(le and not e3plained (y the pharmacoloic properties of
the dru: An e3ample is the individual $ith infectious mononucleosis $ho develops a rash $hen
iven ampicillin:
"m(alance of endoenous flora may occur $hen antimicro(ial aents preferentially suppress the
ro$th of one species of micro(e, allo$in other species to ro$ viorously: 4or e3ample,
candidiasis fre8uently occurs $ith anti(iotic therapy:
"ntolerance may occur in patients $ith altered meta(olism: 4or e3ample, individuals $ho are
slo$ acetylators of the en9yme N0acetyltransferase are more li.ely than others to develop dru0
induced lupus in response to procainamide:
%arisch0Her3heimer phenomenon is a reaction due to (acterial endoto3ins and micro(ial antiens
that are li(erated (y the destruction of microoranisms: 2he reaction is characteri9ed (y fever,
tender lymphadenopathy, arthralias, transient macular or urticarial eruptions, and e3acer(ation
of pree3istin cutaneous lesions: 2he reaction is not an indication to stop treatment (ecause
symptoms resolve $ith continued therapy: 2his reaction can (e seen $ith penicillin therapy for
syphilis, riseofulvin or .etocona9ole therapy for dermatophyte infections, and
diethylcar(ama9ine therapy for oncocerciasis:
=verdosae is an e3aerated response to an increased amount of a medication: 4or e3ample,
increased doses of anticoaulants may result in purpura:
!hototo3ic dermatitis is an e3aerated sun(urn response caused (y the formation of to3ic
photoproducts, such as free radicals or reactive o3yen species +see Media file 10,:
Frequency
United #tate!
Dru eruptions occur in appro3imately 20AH of inpatients and in reater than 1H of outpatients:
Internationa
Dru eruptions occur in appro3imately 20;H of inpatients:
Mortaity.Mor"idity
Most dru eruptions are mild, self0limited, and usually resolve after the offendin aent has (een
discontinued: )evere and potentially life0threatenin eruptions occur in appro3imately 1 in 1000
hospital patients: Mortality rates for erythema multiforme +/M, ma<or are sinificantly hiher:
)tevens0%ohnson syndrome +)%), has a mortality rate of less than AH, $hereas the rate for 2/#
approaches 200;0H1 most patients die from sepsis:
#e/
Adverse cutaneous reactions to drus are more prevalent in $omen than in men:
Age
/lderly patients have an increased prevalence of adverse dru reactions:
)0INI)A0
)ection ; of 11
Authors and /ditors
"ntroduction
*linical
Differentials
&or.up
2reatment
Medication
4ollo$0up
Miscellaneous
Multimedia
'eferences
Hi!tory
2he first step is to revie$ the patientKs complete medication list, includin over0the0counter
supplements: Document any history of previous adverse reactions to drus or foods: *onsider
alternative etioloies, especially viral e3anthems and (acterial infections: /3anthematous
eruptions in children are more li.ely to (e due to a viral infection than another infection1
ho$ever, most such reactions in adults are due to medications:
#ote any concurrent infections, meta(olic disorders, or immunocompromise +e, due to H"5
infection, cancer, chemotherapy, (ecause these increase the ris. of dru eruptions:
"mmunocompromised persons have a 100fold hiher ris. of developin a dru eruption than the
eneral population: Althouh H"5 infection causes profound anery to other immune stimuli, the
fre8uency of dru hypersensitivity reactions, includin severe reactions +e, 2/#,, is mar.edly
increased in H"50positive individuals: !atients $ith advanced H"5 infection +*D@ count I200
cells?SL, have a 100 to A00fold increased ris. of developin an e3anthematous eruption to
sulfametho3a9ole:
#ote and detail the follo$in:
All prescription and over0the0counter drus, includin topical aents, vitamins, and
her(al and homeopathic remedies
2he interval (et$een the introduction of a dru and onset of the eruption
'oute, dose, duration, and fre8uency of dru administration
Use of parenterally administered drus, $hich are more li.ely than oral aents to cause
anaphyla3is
Use of topically applied drus, $hich are more li.ely than other drus to induce delayed0
type hypersensitivity reactions
Use of multiple courses of therapy and proloned administration of a dru, $hich can
cause alleric sensiti9ation
Any improvement after dru $ithdra$al and any reaction $ith readministration
&hy!ica
Althouh most dru eruptions are e3anthematous, different types of dru eruptions are descri(ed:
&ith every dru eruption, it is important to evaluate for certain clinical features that may
indicate a severe, potentially life0threatenin dru reaction, such as 2/# or
hypersensitivity syndrome: )uch features include the follo$in:

o Mucous mem(rane erosions

o 6listers +6listers herald a severe dru eruption:,
o #i.ols.y sin +epidermis slouhs $ith lateral pressure1 indicates serious eruption
that may constitute a medical emerency,
o *onfluent erythema
o Anioedema and tonue s$ellin
o !alpa(le purpura
o ).in necrosis +see Media file 2,
o Lymphadenopathy
o Hih fever, dyspnea, or hypotension
Appreciatin the morpholoy and features of dru eruptions is important: 2his can help
the clinician determine the causative medication and the most appropriate treatment:

o Acneiform: 2his is characteri9ed (y inflammatory papules or pustules that have a

follicular pattern: 2hey are locali9ed primarily on the upper (ody: "n contrast to
acne vularis, comedones are a(sent in acneiform eruptions:
o Acral erythema +erythrodysesthesia,: 2his is a relatively common reaction to
chemotherapy and is characteri9ed (y symmetric tenderness, edema, and
erythema of the palms and soles: "t is thouht to (e a direct to3ic effect on the
s.in: Acral erythema often resolves 20@ $ee.s after chemotherapy is discontinued:
o Acute enerali9ed e3anthematous pustulosis +A7/!,: Acute0onset fever and
enerali9ed scarlatiniform erythema occur $ith many small, sterile, nonfollicular
pustules: 2he clinical presentation is similar to pustular psoriasis, (ut A7/! has
more mar.ed hyperleu.ocytosis $ith neutrophilia and eosinophilia: Most cases
are caused (y drus +primarily anti(iotics, often in the first fe$ days of
administration: A fe$ cases are caused (y viral infections, mercury e3posure, or
U5 radiation: A7/! resolves spontaneously and rapidly, $ith fever and pustules
lastin 7010 days then des8uamation over a fe$ days:
o Dermatomyositisli.e: *utaneous findins include dermatomyositis +e, 7ottron
papules,, (ut patients tend to lac. muscle involvement, associated malinancy,
and antinuclear anti(odies: "mprovement is usually noted after the dru is
$ithdra$n:
o /M: 2his includes a spectrum of diseases +e, /M minor, /M ma<or,1 ho$ever,
many authorities cateori9e )%) and 2/# as /M ma<or and differentiate them (y
(ody surface involvement
o
/M minor 0 =verall, this is a mild disease1 patients are healthy: "t is
characteri9ed (y taret lesions distri(uted predominantly on the
e3tremities +see Media file E, Media file 22,: Mucous mem(rane
involvement may occur (ut is not severe: !atients $ith /M minor recover
fully, (ut relapses are common: Most cases are due to infection $ith
herpes simple3 virus, and treatment and prophyla3is $ith acyclovir is
helpful:
)%): 2his is characteri9ed (y $idespread s.in involvement, lare and
atypical taretoid lesions, sinificant mucous mem(rane involvement,
constitutional symptoms, and slouhin of 10H of the s.in: )%) can (e
caused (y drus and infections +especially those due to ycoplasma
pneumoniae,:
)%)?2/# overlap: /pidermal detachment involves 100;0H of (ody
surface area:
2/#: 2his is a severe s.in reaction that involves a prodrome of painful
s.in +not unli.e sun(urn, 8uic.ly follo$ed (y rapid, $idespread, full0
thic.ness s.in slouhin: "t typically affects ;0H or more the total (ody
surface area +see Media files ;0@,: )econdary infection and sepsis are
ma<or concerns, and pneumonia may develop from aspiration of slouhed
mucosa: Most cases are due to drus: 2he ris. of 2/# in H"50positive
patients is 10000fold hiher than in the eneral population:
o /rythema nodosum: 2his is characteri9ed (y tender, red, su(cutaneous nodules
that typically appear on the anterior aspect of the les: Lesions do not suppurate
or (ecome ulcerated +see Media file 1E,: "t is a reactive process often secondary to
infection, (ut it may (e due to medications, especially oral contraceptives and
sulfonamides:
o /rythroderma: 2his is $idespread inflammation of the s.in +see Media file A,, and
it may result from an underlyin s.in condition, dru eruption, internal
malinancy, or immunodeficiency syndrome: Lymphadenopathy is often noted,
and hepatosplenomealy, leu.ocytosis, eosinophilia, and anemia may (e present:
o 4i3ed dru eruptions: Lesions recur in the same area $hen the offendin dru is
iven +see Media file 7,: *ircular, violaceous, edematous pla8ues that resolve
$ith macular hyperpimentation is characteristic: Lesions occur ;0 minutes to F
hours after dru administration: !erioral and perior(ital lesions may occur, (ut the
hands, feet, and enitalia are the most common locations:
o Hypersensitivity syndrome: 2his is a potentially life0threatenin comple3 of
symptoms often caused (y anticonvulsants: !atients have fever, sore throat, rash,
lymphadenopathy, hepatitis, nephritis, and leu.ocytosis $ith eosinophilia: "t
usually (eins $ithin 10; $ee.s after a ne$ dru is started, (ut it may develop ;
months or later into therapy: Aromatic anticonvulsant drus cross0react +ie,
phenytoin, pheno(ar(ital, car(ama9epine,1 valproic acid is a safe alternative:
o Leu.ocytoclastic vasculitis: 2his is the most common severe dru eruption seen in
clinical practice +see Media file 11,: "t is characteri9ed (y (lanchin erythematous
macules 8uic.ly follo$ed (y palpa(le purpura: 4ever, myalias, arthritis, and
a(dominal pain may (e present: "t typically appears 7021 days after the onset of
dru therapy, and a la(oratory evaluation to e3clude internal involvement is
mandatory:
o Lichenoid: 2his reaction appears similar to lichen planus and may (e severely
pruritic +see Media file 12,: 2he eruption may include ec9ematous or psoriasiform
papules:
o Lupus: Dru0induced systemic lupus erythematosus +)L/, produces symptoms
identical to those of )L/, (ut s.in findins are uncommon: Lesions are also
identical to dru0induced su(acute cutaneous lupus erythematosus +)*L/,, $hich
is characteri9ed (y annular, psoriasiform, nonscarrin lesions in a
photodistri(uted pattern:
o Mor(illiform or e3anthematous: 2his is the most common pattern of dru
eruptions1 it is the 8uintessential dru rash: /3anthem is typically symmetric, $ith
confluent erythematous macules and papules that spare the palms and soles: "t
typically develops $ithin 2 $ee.s after the onset of therapy:
o !seudoporphyria: &hile larely a dru0induced condition, it can also occur $ith
use of tannin (eds and hemodialysis: !atients have (listerin and s.in fraility
that is clinically and patholoically +see Media file 20, identical to that of
porphyria cutanea tarda, (ut hypertrichosis and sclerodermoid chanes are a(sent
and urine and serum porphyrin levels are normal: 2reatment is sun protection and
$ithdra$al of the medication:
o )erum sic.ness and serum sic.nessDli.e: 2hese are type """ hypersensitivity
reactions mediated (y the deposition of immune comple3es in small vessels,
activation of complement, and recruitment of ranulocytes: *utaneous sins
typically (ein $ith erythema on the sides of the finers, hands, and toes and
proress to a $idespread eruption +most often mor(illiform or urticarial,: 5iscera
may (e involved, and fever, arthralia, and arthritis are common: )erum sic.nessD
li.e reactions have a clinical presentation similar to that of serum sic.ness
reactions, $ithout the immune comple3 deposition: 'enal involvement is rare:
)erum sic.nessDli.e reactions usually occur $ith anti(iotic therapy, especially
$ith cefaclor:
o )$eet syndrome +acute fe(rile neutrophilic dermatosis,: 2ender erythematous
papules and pla8ues occur most often on the face, nec., upper trun., and
e3tremities: 2he surface of the lesions may (ecome vesicular or pustular:
)ystemic findins are common and include fever +most often,, arthritis,
arthralias, con<unctivitis, episcleritis, and oral ulcers: La(oratory evaluation
usually reveals an elevated sedimentation rate, neutrophilia, and leu.ocytosis:
)$eet syndrome often occurs in association $ith cancers, inflammatory disorders,
prenancy, and medication use:
o Urticaria: 2his usually occurs as small $heals that may coalesce or may have
cyclical or yrate forms: Lesions usually appear shortly after the start of dru
therapy and resolve rapidly $hen the dru is $ithdra$n +see Media file 1F,: 7iant
urticaria is easily mista.en for /M:
o 5esiculo(ullous: 2hese reactions can resem(le pemphius, (ullous pemphioid,
linear immunolo(ulin A +"A, dermatosis, dermatitis herpetiformis, herpes
estationis, or cicatricial pemphioid: Most causative drus have a thiol roup,
disulfide (onds, or sulfur0containin rins that are meta(oli9ed to thiol forms:
2hiol0induced pemphius tends to resem(le pemphius foliaceus or pemphius
erythematosus1 nonthiol eruptions may resem(le pemphius vularis or
pemphius veetans: Mucosal findins may (e most common $ith nonthiol
drus: 'esults from direct and indirect immunofluorescence may (e positive in
persons $ith dru0induced pemphius and (ullous pemphioid: /ruptions usually
resolve after the inducin dru is discontinued, (ut D0penicillamineDinduced
pemphius may ta.e months to resolve and corticosteroids are often needed:
)au!e!
4i(rosin reactions have (een associated $ith a variety of chemical e3posures: #ephroenic
systemic fi(rosis has (een associated $ith adolinium contrast aents used for M'" studies:
"ndividuals $ith renal failure may have a (uildup adolinium in the s.in and other orans and
may recruit *D;@0positive (one marro$Dderived fi(rocytes into lesional areas: 2o3ic oil
inestion has (een associated $ith morphea, and 2e3ier disease has (een associated $ith
phytomenadione +vitamin0G1, in<ections:
'ates of reactions to commonly used drus

o Amo3icillin 0 A:1H
o 2rimethoprim sulfametho3a9ole 0 @:7H
o Ampicillin 0 @:2H
o )emisynthetic penicillin 0 2:BH
o 6lood +$hole human, 0 2:FH
o !enicillin 7 0 1:EH
o *ephalosporins 0 1:;H
o Ruinidine 0 1:2H
o 7entamicin sulfate 0 1H
o !ac.ed red (lood cells 0 0:FH
o Mercurial diuretics 0 0:BH
o Heparin 0 0:7H
*utaneous reaction rates in patients $ith H"5 infection

o )ulfasala9ine 0 20H
o 2rimethoprim0sulfametho3a9ole 0 1@:BH
o Dapsone 0 ;:1H
o Aminopenicillins 0 B:;H
o !enicillins 0 ;:FH
o Anticonvulsants 0 ;:@H
o !enicillinase0resistant penicillins 0 2:BH
o *ephalosporins 0 2:7H
o Ruinolones 0 2:1H
o Getocona9ole 0 2H
o *lindamycin 0 1:FH
o !rima8uine 0 1:FH
o 2etracycline 0 1:2H
o !entamidine 0 1H
o #)A"Ds 0 0:BH
o /rythromycin 0 0:EH
o Oidovudine 0 0:;H
Drus that commonly cause serious reactions

o Allopurinol
o Anticonvulsants
o #)A"Ds
o )ulfa drus
o 6umetanide
o *aptopril
o 4urosemide
o !enicillamine
o !iro3icam
o 2hia9ide diuretics
Drus unli.ely to cause s.in reactions

o Dio3in
o Meperidine
o Acetaminophen
o Diphenhydramine hydrochloride
o Aspirin
o Aminophylline
o !rochlorpera9ine
o 4errous sulfate
o !rednisone
o *odeine
o 2etracycline
o Morphine
o 'eular insulin
o &arfarin
o 4olic acid
o Methyldopa
o *hlorproma9ine
o )erotonin0specific reupta.e inhi(itors
Drus associated $ith specific morpholoic patterns: +#ote: 2he follo$in is a list of
medications that have (een reported to cause specific types of cutaneous reactions:
Ho$ever, not every possi(le type of dru eruption has (een listed: "n addition, e3clusion
of a dru from the follo$in list does not imply that it is not the cause of a patientKs
eruption: A hih inde3 of suspicion must al$ays (e maintained $hen confronted $ith a
ne$ onset eruption in a patient on multiple medications:,

o Acneiform 0 Amo3apine, corticosteroids +see Media file 1;,, haloens,

haloperidol, hormones, isonia9id, lithium, phenytoin, and tra9odone
o A7/! 0 Most commonly (eta0lactam anti(iotics, macrolides, and mercury1 less
commonly acetaminophen, allopurinol, (ufe3amac, (uphenine, car(ama9epine,
car(utamide, celeco3i(, chloramphenicol, clindamycin, co0trimo3a9ole,
clo(a9am, cyclins +e, tetracycline,, cytara(ine, diltia9em, famotidine,
furosemide, in.o (ilo(a, hydrochlorothia9ide, hydro3ychloro8uine, i(uprofen,
imatini(, imipenem, isonia9id, "5 contrast dye, lopinavir0ritonavir, me3iletine,
morphine, nado3olol, nifedipine, nystatin, olan9apine, phenytoin, pipemidic acid,
pipera9ine, pseudoephedrine, pyrimethamine, 8uinidine, ranitidine, rifampicin,
sal(utiamine, sertraline, simvastatin, streptomycin, ter(inafine, thallium, and
vancomycin
o Alopecia 0 A*/ inhi(itors, allopurinol, anticoaulants, a9athioprine,
(romocriptine, (eta0(loc.ers, cyclophosphamide, didanosine, hormones,
indinavir, #)A"Ds, phenytoin, methotre3ate +M2>,, retinoids, and valproate
o 6ullous pemphioid 0 Ampicillin, D0penicillamine, captopril, chloro8uine,
ciproflo3acin, enalapril, furosemide, neuroleptics, penicillins, phenacetin,
psoralen plus U50A, salicyla9osulfapyridine, sulfasala9ine, and ter(inafine
o Dermatomyositisli.e 0 6*7 vaccine, hydro3yurea +most common,, lovastatin,
omepra9ole, penicillamine, simvastatin, and teafur
o /rythema nodosum 0 /chinacea, haloens, oral contraceptives +most common,,
penicillin, sulfonamides, and tetracycline
o /rythroderma 0 Allopurinol, anticonvulsants, aspirin, (ar(iturates, captopril,
car(ama9epine, cefo3itin, chloro8uine, chlorproma9ine, cimetidine, diltia9em,
riseofulvin, lithium, nitrofurantoin, omepra9ole, phenytoin, )t: %ohnKs $ort,
sulfonamides, and thalidomide
o 4i3ed dru eruptions 0 Acetaminophen, ampicillin, anticonvulsants,
aspirin?#)A"D, (ar(iturates, (en9odia9epines, (utal(ital, cetiri9ine, ciproflo3acin,
clarithromycin, dapsone, de3tromethorphan, do3ycycline, flucona9ole,
hydro3y9ine, lamotriine, loratadine, metronida9ole, oral contraceptives,
penicillins, phenacetin, phenolphthalein, phenytoin, piro3icam, sa8uinavir,
sulfonamides, tetracyclines, ticlopidine, tolmetin, vancomycin, and 9olmitriptan
o Hypersensitivity syndrome 0 Allopurinol, amitriptyline, car(ama9epine, dapsone,
lamotriine, minocycline, #)A"Ds, olan9apine, o3car(a9epine, pheno(ar(ital,
phenytoin, sa8uinavir, spironolactone, sulfonamides, 9alcita(ine, and 9idovudine
o Lichenoid 0 Amlodipine, antimalarials, (eta0(loc.ers, captopril, diflunisal,
diltia9em, enalapril, furosemide, limepiride, old, leflunomide, levamisole, L0
thyro3ine, orlistat, penicillamine, phenothia9ine, pravastatin, proton pump
inhi(itors, rofeco3i(, salsalate, sildenafil, tetracycline, thia9ides, and
ursodeo3ycholic acid
o Linear "A dermatosis 0 Atorvastatin, captopril, car(ama9epine, diclofenac,
li(enclamide, lithium, phenytoin, and vancomycin
o Lupus erythematosus
o
Dru0induced )L/ is most commonly associated $ith hydrala9ine,
procainamide, and minocycline: 6eta0(loc.ers, chlorproma9ine,
cimetidine, clonidine, estroens, isonia9id, lithium, lovastatin,
methyldopa, oral contraceptives, 8uinidine, sulfonamides, tetracyclines,
and tumor necrosis factor +2#4,Dalpha inhi(itors have (een reported:
Dru0induced )*L/ is most commonly associated $ith
hydrochlorothia9ide: *alcium channel (loc.ers, cimetidine, riseofulvin,
leflunomide, ter(inafine, and 2#40alpha inhi(itors have (een reported:
o Mor(illiform +e3anthematous, 0 A*/ inhi(itors, allopurinol, amo3icillin,
ampicillin, anticonvulsants, (ar(iturates, car(ama9epine, cetiri9ine, in.o (ilo(a,
hydro3y9ine, isonia9id, nelfinavir, #)A"Ds, phenothia9ine, phenytoin,
8uinolones, sulfonamides, thalidomide, thia9ides, trimethoprim0sulfametho3a9ole,
and 9alcita(ine
o !emphius
o
2hiols include captopril, D0penicillamine, old sodium thiomalate,
mercaptopropionyllycine, pyritinol, thiama9ole, and thiopronine:
#onthiols include aminophena9one, aminopyrine, a9apropa9one,
cephalosporins, heroin, hydantoin, imi8uimod, indapamide, levodopa,
lysine acetylsalicylate, montelu.ast, o3yphen(uta9one, penicillins,
pheno(ar(ital, phenyl(uta9one, piro3icam, proesterone, propranolol, and
rifampicin:
o !hotosensitivity 0 A*/ inhi(itors, amiodarone, amlodipine, celeco3i(,
chlorproma9ine, diltia9em, furosemide, riseofulvin, lovastatin, nifedipine,
phenothia9ine, piro3icam, 8uinolones, sulfonamides, tetracycline, and thia9ide
o !seudoporphyria 0 Amiodarone, (umetanide, chlorthalidone, cyclosporine,
dapsone, etretinate, A0fluorouracil, flutamide, furosemide,
hydrochlorothia9ide?triamterene, isotretinoin, #)A"Ds +includin nalidi3ic acid
and napro3en,, oral contraceptive pills, and tetracycline
o !soriasis 0 A*/ inhi(itors, aniotensin receptor antaonists, antimalarials, (eta0
(loc.ers, (upropion, calcium channel (loc.ers, car(ama9epine, interferon +"4#,
alfa, lithium, metformin, #)A"Ds, ter(inafine, tetracyclines, valproate sodium,
and venlafa3ine
o )erum sic.ness 0 Antithymocyte lo(ulin for (one marro$ failure, human ra(ies
vaccine, penicillin, pneumococcal vaccine +in A"D) patients,, and vaccines
containin horse serum derivatives
o )erum sic.nessDli.e 0 6eta0lactam anti(iotics, cefaclor +most common,,
minocycline, propranolol, strepto.inase, sulfonamides, and #)A"Ds
o )%) 0 Allopurinol, anticonvulsants, aspirin?#)A"D), (ar(iturates, car(ama9epine,
cimetidine, ciproflo3acin, codeine, didanosine, diltia9em, erythromycin,
furosemide, riseofulvin, hydantoin, indinavir, nitroen mustard, penicillin,
phenothia9ine, phenyl(uta9one, phenytoin, ramipril, rifampicin, sa8uinavir,
sulfonamides, tetracyclines, and trimethoprim0sulfametho3a9ole
o )$eet syndrome 0 All0trans0retinoic acid, celeco3i(, ranulocyte colony0
stimulatin factor, nitrofurantoin, oral contraceptives, tetracyclines, and
trimethoprim0sulfametho3a9ole
o 2/# 0 Alfu9osin, allopurinol, anticonvulsants, aspirin?#)A"Ds, sulfado3ine and
pyrimethamine +4ansidar,, isonia9id, lamotriine, lansopra9ole, letro9ole,
penicillins, phenytoin, pra9osin, sulfonamides, tetracyclines, thalidomide,
trimethoprim0sulfametho3a9ole, and vancomycin
o Urticaria 0 A*/ inhi(itors, alendronate, aspirin?#)A"Ds, (lood products,
cephalosporins, cetiri9ine, clopidorel, de3tran, didanosine, infli3ima(, inhaled
steroids, nelfinavir, opiates, penicillin, peptide hormones, polymy3in, proton
pump inhi(itors, radioloic contrast material, ranitidine, tetracycline, vaccines,
and 9idovudine
o 5asculitis 0 Adalimuma(, allopurinol, aspirin?#)A"Ds, cimetidine, old,
hydrala9ine, indinavir, leflunomide, levoflo3acin, minocycline, montelu.ast,
penicillin, phenytoin, propylthiouracil, proton pump inhi(itors, 8uinolones,
ramipril, sulfonamide, tetracycline, thia9ides, and thiorida9ine
o 5esiculo(ullous +other, 0 A*/ inhi(itors, aspirin?#)A"Ds, (ar(iturates, captopril,
cephalosporins, entacapone, estroen, furosemide, riseofulvin, influen9a vaccine,
penicillamine, penicillins, sertraline sulfonamides, and thia9ides
!sychotropic drus associated $ith specific morpholoic patterns

o Alopecia 0 *ar(ama9epine, fluo3etine, lamotriine, lithium, a(apentin, and

valproic acid
o /M 0 6ar(iturates, car(ama9epine, dia9epam overdose, fluo3etine, a(apentin,
lithium plus tra9odone concurrently, pheno(ar(ital, risperidone, sertraline, and
valproic acid
o Mor(illiform +e3anthematous, 0 Alpra9olam, (ar(iturates, (upropion,
car(ama9epine, chlorproma9ine, desipramine, fluo3etine, lithium, maprotiline,
nefa9odone, risperidone, and tra9odone
o !hotosensitivity 0 All antipsychotics, (ar(iturates, car(ama9epine,
chlorproma9ine, do3epin, imipramine, thiorida9ine, and valproic acid
o !imentation 0 Amitriptyline, car(ama9epine, chlorproma9ine, clo9apine,
dia9epam follo$in derma(rasion, a(apentin, haloperidol, lamotriine,
perphena9ine, and thiorida9ine
o Urticaria 0 6upropion, car(ama9epine, chlordia9epo3ide, fluo3etine, imipramine,
lamotriine, lithium, paro3etine, and tra9odone
o 5asculitis 0 4luo3etine, maprotiline, paro3etine, and tra9odone
*hemotherapeutic aents associated $ith specific morpholoic patterns

o Acneiform 0 *etu3ima(, dactinomycin, erlotini(, fluo3ymesterone, efitini(,

medro3yproesterone, and vin(lastine
o Acral erythema +erythrodysesthesia, 0 *apecita(ine, cisplatin, clofara(ine,
cyclophosphamide, cytara(ine, doceta3el, do3oru(icin, fluorouracil, emcita(ine,
M2>, teafur, and vinorel(ine
o Alopecia
o
All classes of chemotherapeutic aents are associated $ith alopecia:
*ommonly associated drus include al.ylatin aents, anthracyclines,
(leomycin, do3oru(icin, hydro3yurea, M2>, mitomycin, mito3antrone,
vin(lastine, and vincristine:
6usulfan and cyclophosphamide administered in com(ination can cause
permanent hair loss:
o /M 0 6usulfan, chloram(ucil, cyclophosphamide, diethylstil(estrol +D/),,
etoposide, hydro3yurea, mechlorethamine, M2>, mitomycin *, mitotane,
paclita3el, and suramin
o /rythema nodosum 0 6usulfan, D/), and imatini(
o 4i3ed dru eruptions 0 Dacar(a9ine, hydro3yurea, paclita3el, and procar(a9ine
o Hyperpimentation 0 6ischloroethylnitrosourea +6*#U1 carmustine,, (leomycin,
(usulfan, (re8uinar, cisplatin, cyclophosphamide, dactinomycin, daunoru(icin,
doceta3el, do3oru(icin, fluorouracil, fotemustine, hydro3yurea, ifosfamide, M2>,
mithramycin, mito3antrone, nitroen mustard, procar(a9ine, teafur, thiotepa, and
vinorel(ine
o Lichenoid 0 Hydro3yurea, imatini(, and teafur
o Lupus 0 Aminolutethimide, D/), hydro3yurea, leuprolide, and teafur
o Mor(illiform +e3anthematous, 0 6leomycin, car(oplatin, cis0dichloro0trans0
dihydro3y0bis0isopropylamine platinum +*H"!,, chloram(ucil, cytara(ine,
doceta3el, D/), do3oru(icin, etoposide, A0fluorouracil, hydro3yurea, M2>,
mitomycin *, mitotane, mito3antrone, paclita3el, pentostatin, procar(a9ine,
suramin, and thiotepa
o 2/# 0 Asparainase, (leomycin, chloram(ucil, cladri(ine, cytara(ine,
do3oru(icin, A0fluorouracil, M2>, plicamycin, procar(a9ine, and suramin
o Urticaria 0 Amsacrine, (leomycin, (usulfan, car(oplatin, chloram(ucil, cisplatin,
cyclophosphamide, cytara(ine, daunoru(icin, dia9i8uone, didemnin, D/),
doceta3el, do3oru(icin, epiru(icin, etoposide, A0fluorouracil, mechlorethamine,
melphalan, M2>, mitomycin *, mitotane, mito3antrone, paclita3el, pentostatin,
procar(a9ine, teniposide, thiotepa, trimetre3ate, vincristine, and 9inostatin
o 5asculitis 0 6usulfan, cyclophosphamide, cytara(ine, he3amethylene
(isacetamide +HM6A,, hydro3yurea, imatini(, levamisole, E0mercaptopurine,
M2>, mito3antrone, ritu3ima(, and tamo3ifen
*utaneous reactions to cyto.ine therapy

o /rythropoietin 0 A(normal hair ro$th, locali9ed rash, palpe(ral edema, and

$idespread ec9ema
o 7ranulocyte colony stimulatin factor 0 /3acer(ation of pree3istin psoriasis,
leu.ocytoclastic, locali9ed erythema, locali9ed pruritus, )$eet syndrome, and
vasculitis
o 7ranulocyte macrophae colony0stimulatin factor 0 Alopecia, epidermolysis,
e3acer(ation of vasculitis, e3foliative dermatitis, flushin, locali9ed erythema,
locali9ed $heals, maculopapular eruptions, pruritus, purpura, and urticaria
o "4#0alfa 0 Alopecia, anasarca, cutaneous vascular lesions, eosinophilic fasciitis,
e3acer(ation of pree3istin herpes la(ialis, facial erythema, fi3ed dru eruption,
hyperpimentation, nummular ec9ema, paraneoplastic pemphius, pruritus,
psoriasis, sarcoidosis, )L/, urticaria, and 3erostomia
o "4#0(eta 0 4atal pemphius vularis +$hen used in com(ination $ith interleu.in
+"L,D2, locali9ed reactions +common,, and urticaria
o "4#0amma 0 "ncreased relapses in melanoma and locali9ed inflammation
o "L01alpha 0 Mucositis, phle(itis, )h$art9man reaction, and 3erostomia
o "L01(eta 0 /rythema at surical $ound sites, phle(itis, and rash
o "L02 0 6listers, cutaneous ulcers, des8uamation, erythema, erythema nodosum,
erythroderma, e3acer(ation of autoimmune s.in disorders, flushin,
hypersensitivity to iodine contrast material, necrosis, pruritus, teloen effluvium,
2/#, and urticaria
o "L0; 0 4acial flushin, hemorrhaic rash, throm(ophle(itis, and urticaria
o "L0@ 0 4acial and peripheral edema, 7rover disease, and papular rash
o "L0E 0 Diffuse erythematous scalin macules and papules
o 2#40alpha 0 /rythroderma and locali9ed erythema
DIFFERENTIA0#
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Acute 4e(rile #eutrophilic Dermatosis
*ontact Dermatitis, Alleric
*ontact Dermatitis, "rritant
/rythema Multiforme
/rythema #odosum
/rythroderma +7enerali9ed /3foliative Dermatitis,
7ianotti0*rosti )yndrome +!apular Acrodermatitis of *hildhood,
7raft 5ersus Host Disease
Hypersensitivity 5asculitis +Leu.ocytoclastic 5asculitis,
Lichen !lanus
Measles, 'u(eola
!ityriasis 'osea
!orphyria *utanea 2arda
!soriasis, !ustular
'u(ella
)yphilis
Urticaria, Acute
Urticaria, *hronic
Other &ro"em! to "e )on!idered
Autoimmune (listerin disease
/3acer(ation of pree3istin cutaneous disease
"nfection +viral Mmost commonN, (acterial, funal,
WORKU&
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0a" #tudie!
History and physical e3amination are often sufficient for dianosin mild asymptomatic
eruptions:
)evere or persistent eruptions may re8uire further dianostic testin:

o 6iopsy can (e helpful in confirmin the dianosis of a dru eruption +e, (y

sho$in eosinophils in mor(illiform eruptions or numerous neutrophils $ithout
vasculitis in persons $ith )$eet syndrome,:
o *6* count $ith differential may sho$ leu.openia, throm(ocytopenia, and
eosinophilia in patients $ith serious dru eruptions:
o )erum chemistry studies may (e useful: Liver involvement leadin to death can
occur in persons $ith hypersensitivity syndromes: )pecial attention should (e
paid to the electrolyte (alance and renal and?or hepatic function indices in patients
$ith severe reactions such as )%), 2/#, or vasculitis:
o Anti(ody and?or immunoseroloy tests may (e ordered: Antihistone anti(odies
are noted in persons $ith dru0induced )L/, $hereas anti0'o?))0A anti(odies are
most common in persons $ith dru0induced )*L/:
o Direct cultures may (e needed to investiate a primary infectious etioloy or
secondary infection:
o Urinalysis, stool uaiac tests, and chest radioraphy are important for patients
$ith vasculitis:
Imaging #tudie!
*hest radioraphy, alon $ith urinalysis and stool uaiac tests, is important for patients
$ith vasculitis:
Other Te!t!
'echallene tests (y means of s.in pric. or patch testin to confirm the causative aent is
of limited value:
).in tests may (e ha9ardous to patients $ho have had severe reactions:
&ith the possi(le e3ception of A7/!, patch tests have a lo$ sensitivity and specificity
and are not useful:
Hi!toogic Finding!
"n some cases, (iopsy may (e helpful in esta(lishin a dianosis of a dru reaction:
Histopatholoy of an e3anthematous dru eruption may sho$ (oth superficial and deep
perivascular inflammatory cell infiltrates: /osinophils in the infiltrate suest such a dru
eruption +see Media file 21,:
"n patients $ith )$eet syndrome, (iopsy reveals edema of the superficial dermis and a dense
infiltrate of neutrophils: Leu.ocytoclasia may (e present, (ut vasculitis is a(sent:
Histopatholoy of 2/# sho$s su(epidermal split, full0thic.ness epidermal necrosis and a sparse
perivascular lymphocytic infiltrate +see Media file 20,:
TREATMENT
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Medica )are
2he ultimate oal is al$ays to discontinue the offendin medication if possi(le:
"ndividuals $ith dru eruptions are often the most ill patients ta.in the most
medications, many of $hich are essential for their survival: Ho$ever, all nonessential
medications should (e limited: =nce the offendin dru has (een identified, it should (e
promptly discontinued: Gno$lede of the common eruption inducinDmedications may
help in identifyin the offendin dru:
!atients can possi(ly continue to (e treated throuh mor(illiform eruptions +ie, continue
medication even in patients $ith a rash,: 2he eruption often resolves, especially if the
individual is (ein treated $ith antihistamines: Most authorities (elieve that
e3anthematous dru eruptions are not a precursor to severe reactions, such as 2/#:
#evertheless, all patients $ith severe mor(illiform eruptions should (e monitored for
mucous mem(rane lesions, (listerin, and s.in slouhin:
2reatment of a dru eruption depends on the specific type of reaction: 2herapy for
e3anthematous dru eruptions is supportive in nature: 4irst0eneration antihistamines are
used 2@ h?d: Mild topical steroids +e, hydrocortisone, desonide, and moisturi9in lotions
are also used, especially durin the late des8uamative phase:
)evere reactions, such as )%), 2/#, and hypersensitivity reactions, $arrant hospital
admission: 2/# is (est manaed in a (urn unit $ith special attention iven to electrolyte
(alance and sins of secondary infection: 6ecause adhesions can develop and result in
(lindness, evaluation (y an ophthalmoloist is mandatory: "n addition, mountin
evidence indicates that intravenous immunolo(ulin +"5"7, may improve outcomes for
2/# patients:
Hypersensitivity syndrome, a systemic reaction characteri9ed (y fever, sore throat, rash,
and internal oran involvement, is potentially life threatenin: 2imely reconition of the
syndrome and immediate discontinuation of the anticonvulsant or other offendin dru
are crucial: !atients may re8uire liver transplantation if the dru is not stopped in time:
2reatment $ith systemic corticosteroids has (een advocated:
MEDI)ATION
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2herapy for most dru eruptions is mainly supportive in nature: Mor(illiform eruptions are
treated $ith oral antihistamines and topical steroids: "5"7 is currently the most common aent
used to treat 2/#: *yclosporine may also have a role in the treatment of 2/#: !rednisone may
(e used in the treatment of hypersensitivity syndrome $ith heart and lun involvement, severe
serum sic.nessDli.e reaction, and )$eet syndrome:
Drug )ategory+ First-generation antihistamines
2hese aents antaoni9e H1 receptors and (loc. release of histamine: 2hey provide symptomatic
relief of pruritus and help improve eruptions:
Drug Name
Hydro3y9ine H*l +An3anil, Atara3, Ato9ine,
Durra3, 5istaril,
De!cri-tion
Antaoni9es H1 receptors in periphery: May
suppress histamine activity in su(cortical *#):
Availa(le as 100, 2A0, A00, or 1000m ta(:
Adut Do!e 2A m != 8Eh
&ediatric Do!e 10 m?A mL syr, 0:A01 m?.?d != 8id
)ontraindication! Documented hypersensitivity
Interaction!
*#) depression may increase $ith alcohol or other
*#) depressants +e, meperidine, (ar(iturates,
&regnancy
* 0 )afety for use durin prenancy has not (een
esta(lished:
&recaution!
*linical e3acer(ations of porphyria +may not (e
safe in porphyria,1 /*7 a(normalities +alterations
in 2 $aves, may occur1 may cause dro$siness1 not
recommended in early prenancy or (reastfeedin
Drug Name
Diphenhydramine H*l +6enadryl, 6enylin,
Diphen, AllerMa3,
De!cri-tion
4or symptomatic relief of alleric symptoms
caused (y release of histamine in immune
reactions:
Adut Do!e 2A0A0 m ta( != 8@0Eh
&ediatric Do!e 12:A m?A mL syr, A m?.?d != divided 8@0Eh
)ontraindication! Documented hypersensitivity1 MA="s
Interaction!
!otentiates effect of *#) depressants1 (ecause of
alcohol content, do not administer syr form to
patient ta.in medications that can cause
disulfiramli.e reactions
&regnancy
* 0 )afety for use durin prenancy has not (een
esta(lished:
&recaution!
May e3acer(ate anle0closure laucoma,
hyperthyroidism, peptic ulcer, and urinary tract
o(struction
Drug )ategory+ Second-generation antihistamines, nonsedating
2hese aents cause less, if any, dro$siness than first0eneration aents:
Drug Name Loratadine +*laritin,
De!cri-tion
)electively inhi(its peripheral histamine H1
receptors:
Adut Do!e 10020 m != 8d
&ediatric Do!e
I2 years: #ot esta(lished
20E years: A m != 8d
JE years: Administer as in adults
)ontraindication! Documented hypersensitivity
Interaction!
Getocona9ole, erythromycin, procar(a9ine, and
alcohol may increase levels
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution!
)tart at lo$ dose in renal and liver impairment1
caution in (reastfeedin
Drug )ategory+ Corticosteroids
2opical aents provide symptomatic relief of pruritus: )ystemic steroids are used in persons $ith
hypersensitivity syndrome, severe serum sic.nessDli.e reactions, and )$eet syndrome:
Drug Name Desonide 0:0AH cream, ointment, lotion
De!cri-tion
4or inflammatory dermatosis responsive to
steroids1 decreases inflammation (y suppressin
miration of !M# leu.ocytes and reversin
capillary permea(ility:
Adut Do!e Apply sparinly 20@ times?d
&ediatric Do!e Apply as in adults
)ontraindication!
Documented hypersensitivity1 funal, viral, and
(acterial s.in infections
Interaction! #one reported
&regnancy
* 0 )afety for use durin prenancy has not (een
esta(lished:
&recaution!
!roloned use, application over lare surface areas,
application of potent steroids, and occlusive
dressins may increase systemic a(sorption and
may result in *ushin syndrome, reversi(le H!A0
a3is suppression, hyperlycemia, and lycosuria
Drug Name !rednisone +Deltasone, =rasone, )terapred,
De!cri-tion
"mmunosuppressant for treatment of immune
disorders1 may decrease inflammation (y reversin
increased capillary permea(ility and suppressin
!M# activity1 availa(le in 2:A0, A0, 100, 200, or A00
m ta(:
Adut Do!e 102 m?. != 8d initially, taper over @0E $.
&ediatric Do!e
102 m?. != 8d or divided (id?8id1 taper over 2
$. as symptoms resolve
)ontraindication! A(solute: )ystemic funal infection, herpes
simple3 .eratitis, hypersensitivity +usually $ith
corticotropin (ut occasionally noted $ith "5
preparations,
'elative: hypertension, active tu(erculosis,
conestive heart failure, prior psychosis, positive
intradermal positive protein derivative te3t,
laucoma, severe depression, dia(etes mellitus,
active peptic ulcer disease, cataracts, osteoporosis,
recent (o$el anastomosis, prenancy
Interaction!
*oadministration $ith estroens may decrease
clearance1 $hen used $ith dio3in, diitalis
to3icity secondary to hypo.alemia may increase1
pheno(ar(ital, phenytoin, and rifampin may
increase meta(olism of lucocorticoids +consider
increasin maintenance dose,1 monitor for
hypo.alemia $ith coadministration of diuretics
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution!
A(rupt discontinuation may cause adrenal crisis1
hyperlycemia, edema, osteonecrosis, myopathy,
peptic ulcer disease, hypo.alemia, osteoporosis,
euphoria, psychosis, myasthenia ravis, ro$th
suppression, and infections may occur
Drug )ategory+ Immunoglobulins
2hese aents are used to treat 2/#:
Drug Name
"ntravenous immunolo(ulin +7ammaard,
7amimune,
De!cri-tion
6lood product prepared from pooled plasma of
healthy donors: 4ollo$in features are possi(ly
relevant to efficacy: neutrali9ation of circulatin
myelin anti(odies throuh anti0idiotypic
anti(odies1 do$n0reulation of proinflammatory
cyto.ines, includin "4#0amma1 (loc.ade of 4c
receptors on macrophaes1 suppression of inducer
2 and 6 cells and aumentation of 20suppressor
cells1 (loc.ade of complement cascade1 promotion
of remyelination1 and 10H increase in *)4 "7:
Adut Do!e 1 ?. "5 8d for ; consecutive days
&ediatric Do!e Administer as in adults
)ontraindication!
Documented hypersensitivity1 "A deficiency1 anti0
"/?"7 anti(odies
Interaction! #one reported
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution!
*onsider chec.in serum "A level (efore therapy
and usin "A0depleted "5"7 +707ard0)D, if
indicated1 may increase serum viscosity and
throm(oem(olic events1 miraine headache
reported1 10H increased ris. of aseptic meninitis1
increased ris. of urticaria, pruritus, or petechiae 20
A d after infusion, $hich may last I1 mo1 increased
ris. of renal tu(ular necrosis in elderly persons,
dia(etes, volume depletion, or pree3istin .idney
disease1 can alter la(oratory values +e, elevated
antiviral or anti(acterial anti(ody titers for 1 mo,
E0fold increase in /)' for 20; $.,1 apparent
hyponatremia
FO00OW1U&
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&rogno!i!
4ull recovery $ithout any complications is e3pected for most dru eruptions:
/ven after the responsi(le aent is discontinued, dru eruptions may clear slo$ly or
$orsen over the ne3t fe$ days: 2he time re8uired for total clearin may (e 102 $ee.s or
loner:
!atients $ith e3anthematous eruptions should (e counseled to e3pect mild des8uamation
as the rash resolves:
!atients $ith hypersensitivity syndrome are at ris. of (ecomin hypothyroid, usually
$ithin the first @012 $ee.s after the reaction:
2he pronosis for patients $ith 2/# is uarded: )carrin, (lindness, and death are
possi(le:
&atient Education
"f the responsi(le dru is identified, advise the patient to avoid that dru in the future:
*learly la(el the medical record: Advise patients to carry a card or some other form of
emerency identification in their $allets that lists dru alleries and?or intolerances,
especially if they have had a severe reaction:
Advise patients a(out drus that are cross0reactive and a(out drus that must (e avoided:
4or e3ample, penicillin allery reactions have cross0reactivity $ith cephalosporins,
phenytoin hypersensitivity syndrome has cross0reactivity $ith pheno(ar(ital and
car(ama9epine, and sulfonamide reactions cross0react $ith other sulfa0containin drus:
4or e3cellent patient education resources, visit eMedicineKs Allery *enter: Also, see
eMedicineKs patient education article Dru Allery:
MI#)E00ANEOU#
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Medica.0ega &it3a!
Dru reactions are a common reason for litiation: #ot $arnin a patient a(out potential
adverse effects, prescri(in a medicine to a previously sensiti9ed patient, and prescri(in
a related medication $ith cross0reactivity are the most common medicoleal pitfalls:
4ailure to dianose a reaction to medication may prompt litiation: "f anticonvulsant
hypersensitivity is not reconi9ed early and the dru is not $ithdra$n promptly, death or
liver failure may result:
/arly reconition, transfer to a (urn unit, and possi(ly "5"7 may decrease the mortality
and mor(idity of )%) and 2/#:
MU0TIMEDIA
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Media file 1: Mor"ii3orm drug eru-tion4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 2: War3arin 5)oumadin6 necro!i! in7o7ing the eg4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file ;: To/ic e-iderma necroy!i!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file @: #te7en!1'ohn!on !yndrome4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file A: Erythroderma4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file E: Erythema muti3orme4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 7: Fi/ed drug eru-tion4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file F: Fi/ed drug eru-tion in7o7ing the -eni!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file B: Ora uceration! in a -atient recei7ing cytoto/ic thera-y4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 10: &hototo/ic reaction a3ter u!e o3 a tanning "ooth4 Note !har- cuto33 $here
cothing "oc(ed e/-o!ure4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 11: 2a!cuitic reaction on the eg!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 12: 0ichen -anu! on the nec(4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1;: #teroid acne4 Note -u!tue! and a"!ence o3 comedone!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1@: Drug reaction to hydro/ychoroquine 5&aqueni64
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1A: Urticaria4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1E: Erythema nodo!um4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 17: )on3uent necro!i! o3 the e-idermi! in to/ic e-iderma necroy!i!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1F: &eri7a!cuar mi/ed in3ammatory in3itrate $ith eo!ino-hi!
characteri!tic o3 drug1induced urticaria4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1B: ,io-!y o3 -!eudo-or-hyria !ho$! a !u"e-iderma "i!ter $ith itte to no
in3ammation4
5ie$ 4ull )i9e "mae
Media type: "mae
Media file 20: )on3uent necro!i! o3 the e-idermi! in to/ic e-iderma necroy!i!4
5ie$ 4ull )i9e "mae
Media type: "mae
Media file 21: #u-er3icia -eri7a!cuar in3ammatory in3itrate $ith numerou!
eo!ino-hi! characteri!tic o3 an e/anthematou! drug eru-tion4
5ie$ 4ull )i9e "mae
Media type: "mae
Media file 22: Target e!ion! o3 erythema muti3orme4
5ie$ 4ull )i9e "mae
Media type: "mae
REFEREN)E#
)ection 11 of 11
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Antonov D, Ga9and<ieva %, /tuov D, et al: Dru0induced lupus erythematosus: Clin
'ermatol: Mar0Apr 200@122+2,:1A70EE: MMedlineN:
Asnis LA, 7aspari AA: *utaneous reactions to recom(inant cyto.ine therapy: J Am Aca!
'ermatol: )ep 1BBA1;;+;,:;B;0@101 8ui9 @1002: MMedlineN:
6ar(aud A: Dru patch testin in systemic cutaneous dru allery: +o(icology: Apr
1A 200A120B+2,:20B01E: MMedlineN:
6eylot *, Doutre M), 6eylot06arry M: Acute enerali9ed e3anthematous
pustulosis: Semin Cutan e! Surg: Dec 1BBE11A+@,:2@@0B: MMedlineN:
6or. G: Adverse dru reactions: "n: Demis D%, ed: *linical Dermatoloy: -ol ..
Phila!elphia/ Pa0 &ippincott1Ra%en2 1334:
6reathnach )M, Hintner H: Adverse Dru 'eactions and the ).in: &on!on/ Englan!0
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6renner ), 6ialy07olan A, 'uocco 5: Dru0induced pemphius: Clin 'ermatol: May0
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*ampos04ernande9 Mdel M, !once0De0Leon0'osales ), Archer0Du(on *, =ro9co0
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*arr A, 7arsia ': Manain H"5: !art ;: Mechanisms of disease: ;:A Ho$ H"5 leads to
hypersensitivity reactions: e! J Aust: 4e( 1B 1BBE11E@+@,:2270B: MMedlineN:
*arr A, *ooper DA: !athoenesis and manaement of H"50associated dru
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*lar. 6M, Gotti 7H, )hah AD, *oner #7: )evere serum sic.ness reaction to oral and
intramuscular penicillin: Pharmacotherapy: May 200E12E+A,:70A0F: MMedlineN:
*oom(s ''A, 7ell !7H: *lassification of alleric reactions responsi(le for clinical
hypersensitivity and disease: Clin Aspects Immunol: 1BEF1A7A0BE:
*oopman )A, %ohnson 'A, !latt ', )tern '): *utaneous disease and dru reactions in
H"5 infection: N Engl J e!: %un 10 1BB;1;2F+2;,:1E700@: MMedlineN:
Dacey M%, *allen %!: Hydro3yurea0induced dermatomyositis0li.e eruption: J Am Aca!
'ermatol: Mar 200;1@F+;,:@;B0@1: MMedlineN:
Daoud M), )chan(acher *4, Dic.en *H: 'econi9in cutaneous dru eruptions:
'eaction patterns provide clues to causes: Postgra! e!: %ul 1BBF110@+1,:1010@, 1070F,
11@0A: MMedlineN:
Di.a /, 5arotti *, 6arda99i 4, Mai(ach H": Dru0induced psoriasis: an evidence0(ased
overvie$ and the introduction of psoriatic dru eruption pro(a(ility score: Cutan *cul
+o(icol: 200E12A+1,:1011: MMedlineN:
/llehausen !, /lsner !, 6ur 7: Dru0induced lichen planus: Clin 'ermatol: May0
%un 1BBF11E+;,:;2A0;2: MMedlineN:
4it9patric. %/: #e$ histopatholoic findins in dru eruptions: 'ermatol
Clin: %an 1BB2110+1,:1B0;E: MMedlineN:
4rench L/, 2rent %2, Gerdel 4A: Use of intravenous immunolo(ulin in to3ic epidermal
necrolysis and )tevens0%ohnson syndrome: our current understandin: Int
Immunopharmacol: Apr 200E1E+@,:A@;0B: MMedlineN:
7reen %%, Manders )M: !seudoporphyria: J Am Aca! 'ermatol: %an 20011@@+1,:1000
F: MMedlineN:
7reen(erer !A: F: Dru allery: J Allergy Clin Immunol: 4e( 200E1117+2 )uppl Mini0
!rimer,:)@E@070: MMedlineN:
Hasan 2, %ansen *2: /rythroderma: a follo$0up of fifty cases: J Am Aca!
'ermatol: %un 1BF;1F+E,:F;E0@0: MMedlineN:
Hun9i.er 2, Gun9i U!, 6raunsch$ei ), et al: *omprehensive hospital dru monitorin
+*HDM,: adverse s.in reactions, a 200year survey: Allergy: Apr 1BB71A2+@,:;FF0
B;: MMedlineN:
"annini !, Mandell L, 4elminham %, et al: Adverse cutaneous reactions and drus: a
focus on antimicro(ials: J Chemother: Apr 200E11F+2,:1270;B: MMedlineN:
Geet ", Meyaard L, 6oucher /, et al: Alleric reactions to cotrimo3a9ole correlate $ith
decreased 20cell reactivity compati(le $ith a 2h1 to 2h2 shift Ma(str !=0A1B00@0@N: Int
Con, AI'S: 1BB;1B +1,:202:
Gramer M), Leventhal %M, Hutchinson 2A, 4einstein A': An alorithm for the
operational assessment of adverse dru reactions: ": 6ac.round, description, and
instructions for use: JAA: Au 17 1B7B12@2+7,:E2;0;2: MMedlineN:
Lerch M, !ichler &%: 2he immunoloical and clinical spectrum of delayed dru0induced
e3anthems: Curr *pin Allergy Clin Immunol: =ct 200@1@+A,:@110B: MMedlineN:
Litt %O: Dru /ruption 'eference Manual 2002: Ne6 8or5/ N80 Parthenon2 7997:
MacMorran &), Grahn L/: Adverse cutaneous reactions to psychotropic
drus: Psychosomatics: )ep0=ct 1BB71;F+A,:@1;022: MMedlineN:
Mayora *, !ena '', 6lanca0Lope9 #, et al: Monitorin the acute phase response in
non0immediate alleric dru reactions: Curr *pin Allergy Clin
Immunol: Au 200E1E+@,:2@B0A7: MMedlineN:
McGenna %G, Leiferman GM: Dermatoloic dru reactions: Immunol Allergy Clin North
Am: Au 200@12@+;,:;BB0@2;, vi: MMedlineN:
Moc.enhaupt M, )chopf /: /pidemioloy of dru0induced severe s.in reactions: Semin
Cutan e! Surg: Dec 1BBE11A+@,:2;E0@;: MMedlineN:
#ien ), Gno$les )', )hear #H: Dru eruptions: approachin the dianosis of dru0
induced s.in diseases: J 'rugs 'ermatol: %un 200;12+;,:27F0BB: MMedlineN:
!a8uet !, !ierard 7/, Ruatresoo9 !: #ovel treatments for dru0induced to3ic epidermal
necrolysis +LyellKs syndrome,: Int Arch Allergy Immunol: Mar 200A11;E+;,:20A0
1E: MMedlineN:
!ereira 4A, Mudil A5, 'osmarin DM: 2o3ic epidermal necrolysis: J Am Aca!
'ermatol: 4e( 20071AE+2,:1F10200: MMedlineN:
'evu9 %, 5aleyrie0Allanore L: Dru reactions: "n: Dermatoloy: -ol 1. Phila!elphia/ Pa0
osby2 799.0: ;;;0A;:
'oe /, 7arcia Muret M!, Marcuello /, et al: Description and manaement of cutaneous
side effects durin cetu3ima( or erlotini( treatments: a prospective study of ;0 patients: J
Am Aca! 'ermatol: )ep 200E1AA+;,:@2B0;7: MMedlineN:
'ou<eau %*, Gelly %!, #aldi L, et al: Medication use and the ris. of )tevens0%ohnson
syndrome or to3ic epidermal necrolysis: N Engl J e!: Dec 1@ 1BBA1;;;+2@,:1E000
7: MMedlineN:
'ou<eau %*, 6ioulac0)ae !, 6ourseau *, et al: Acute enerali9ed e3anthematous
pustulosis: Analysis of E; cases: Arch 'ermatol: )ep 1BB11127+B,:1;;;0F: MMedlineN:
)hapiro L/, )hear #H: Mechanisms of dru reactions: the meta(olic trac.: Semin Cutan
e! Surg: Dec 1BBE11A+@,:217027: MMedlineN:
)hipley D, =rmerod AD: Dru0induced urticaria: 'econition and treatment: Am J Clin
'ermatol: 200112+;,:1A10F: MMedlineN:
)tern '), )tein(er LA: /pidemioloy of adverse cutaneous reactions to
drus: 'ermatol Clin: %ul 1BBA11;+;,:EF10F: MMedlineN:
)usser &), &hita.er0&orth DL, 7rant0Gels %M: Mucocutaneous reactions to
chemotherapy: J Am Aca! 'ermatol: Mar 1BBB1@0+;,:;E70BF1 8ui9 ;BB0@00: MMedlineN:
2san.ov #, Anelova ", Ga9and<ieva %: Dru0induced psoriasis: 'econition and
manaement: Am J Clin 'ermatol: May0%un 200011+;,:1AB0EA: MMedlineN:
5ervloet D, Durham ): Adverse reactions to drus: #J: May 1E 1BBF1;1E+71@;,:1A110
@: MMedlineN:
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Aca! 'ermatol: 4e( 20021@E+2,:2F@0B;: MMedlineN:
&arnoc. %G, Morris D&: Adverse cutaneous reactions to antidepressants: Am J Clin
'ermatol: 20021;+A,:;2B0;B: MMedlineN:
&arnoc. %G, Morris D&: Adverse cutaneous reactions to mood sta(ili9ers: Am J Clin
'ermatol: 200;1@+1,:210;0: MMedlineN:
&olf ', =rion /, Marcos 6, Mat9 H: Life0threatenin acute adverse cutaneous dru
reactions: Clin 'ermatol: Mar0Apr 200A12;+2,:1710F1: MMedlineN:
&olverton )/: Update on cutaneous dru reactions: A!% 'ermatol: 1BB711;:EA0
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Hy-ereo!ino-hiic #yndrome
Article Last Updated: Mar 2F, 200F
AUTHOR AND EDITOR INFORMATION
)ection 1 of 11
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Author: Noah # #chein3ed, MD, 'D, FAAD, Assistant *linical !rofessor, Department of
Dermatoloy, *olum(ia University1 *onsultin )taff, Department of Dermatoloy, )t Lu.eKs
'oosevelt Hospital *enter, 6eth "srael Medical *enter, #e$ -or. /ye and /ar "nfirmary1 !rivate
!ractice
#oah ) )cheinfeld is a mem(er of the follo$in medical societies: American Academy of
Dermatoloy
*oauthor+s,: Fei/ Urman, MD, )taff !hysician, Department of Dermatoloy, )t Lu.eKs
'oosevelt Hospital *enter
/ditors: Ta(e8i Ni!hi(a$a, MD, /meritus !rofessor, Department of Dermatoloy, Geio
University )chool of Medicine1 Director, )amoncho Dermatoloy *linic1 Manain Director,
2he &a.sman 4oundation of %apan "nc1 Da7id F ,uter, MD, !rofessor of Dermatoloy, 2e3as
ATM University *ollee of Medicine1 Director, Division of Dermatoloy, )cott and &hite
*linic1 Director Dermatoloy 'esidency 2rainin !roram, )cott and &hite *linic1 'e33rey &
)aen, MD, !rofessor of Medicine, *hief, Division of Dermatoloy, University of Louisville
)chool of Medicine1 )atherine *uir(, MD, *linical Assistant !rofessor, Department of
Dermatoloy, 6ro$n University1 Dir( M E!ton, MD, Director, Department of Dermatoloy,
7eisiner Medical *enter
Author and Editor Di!co!ure
#ynonym! and reated (ey$ord!+ idiopathic hypereosinophilic syndrome, H"), H/),
eosinophilic leu.emia, eosinophilia
INTRODU)TION
)ection 2 of 11
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,ac(ground
Hypereosinophilic syndrome +H/), encompasses a $ide rane of clinical manifestations sharin
; features defined (y *husid et al
1
: +1, a peripheral eosinophil count of reater than 1:A > 10
B
?L
for loner than E months1 +2, evidence of oran involvement, thus e3cludin (enin eosinophilia1
and +;, an a(sence of other causes of eosinophilia, such as parasite infestation +most common
cause of eosinophilia $orld$ide,, allery +most common cause of eosinophilia in the United
)tates,, malinancy, and collaen0vascular disease:
2he eMedicine !ediatric article Hypereosinophilic )yndrome and the Hematoloy article
Hypereosinophilic )yndrome may (e of interest: Additionally, see the Medscape Heart 4ailure
'esource *enter and the *ardiometa(olic 'is. 4actor Manaement 'esource *enter:
&atho-hy!ioogy
H/) etioloy can involve +1, primitive involvement of myeloid cells, essentially due to the
occurrence of an interstitial chromosomal deletion on (and @812 leadin to the creation of the
)IP1&11P'G)RA fusion ene +4?!
U
variant,, or +2, increased interleu.in +"L,A production (y a
clonally e3panded 20cell population +lymphocytic variant,, most fre8uently characteri9ed (y a
*D;
0
*D@
U
phenotype:
2
Multiple cyto.ines stimulate eosinophil production, includin "L0;, ranulocyte0macrophae
colony0stimulatin factor +7M0*)4,, and "L0A:
;
"n ; patients $ith 20cell lymphomas,
eosinophilia has (een correlated $ith increased production of these cyto.ines (y the lymphomas:
"L0; and 7M0*)4 act on other (one marro$Dderived lineaes, $hereas the stimulatory activity
of "L0A appears to (e limited to eosinophils and thus suests it to (e the dominant factor in
eosinophil proliferation: At present, the source of "L0A in H/) has not (een definitively
determined, (ut evidence points to increased production (y *D@
U
20lymphocyte clones:
Ho$ever, "L0A m'#A and protein have (een found in eosinophils1 therefore, the increase in this
cyto.ine cannot (e attri(uted merely to 2 cells: Also, (ecause some patients $ith H/) have
concomitant neutrophilia, factors other than "L0A are li.ely involved: 7M0*)4 and "L0; have
(een sho$n to (e produced (y eosinophils, and 7M0*)4 production $as demonstrated in the 20
cell clones from patients $ith H/):
/osinophils in H/) infiltrate multiple orans $here they inflict tissue damae throuh the
release of ranule proteins, includin eosinophil pero3idase, ma<or (asic protein, eosinophil0
derived neuroto3in, and eosinophil cationic protein: 2hey also release proinflammatory cyto.ines
+ie, interleu.in 1 alpha, tumor necrosis factorDalpha, interleu.in E, interleu.in F, "L0;, "L0A, 7M0
*)4, macrophae inflammatory protein,, $hich attract more eosinophils and other inflammatory
cells to the area: *ardiac involvement is the most common cause of mortality in H/): "n the
heart, the infiltration (y eosinophils results in endomyocardial fi(rosis, $ith su(se8uent
development of conestive heart failure +*H4, and death: 2his infiltration is necessary for tissue
damae to occur (ecause patients $ith peripheral eosinophilia due to other causes +e,
eosinophilic pneumonia, do not develop patholoy similar to H/):
4ip10li.e10platelet0derived ro$th factor receptor alpha chain +)IP1&11P'G)RA, mutation has
(een descri(ed in adult patients $ith H/): )pecifically, a novel oncoenic mutation +)IP1&11
P'G)RA,, $hich results in a constitutively activated platelet0derived ro$th factor receptor0
alpha +P'G)RA,, has (een invaria(ly associated $ith a primary eosinophilic disorder:
!ardanani et al
@
e3amined (oth the prevalence and the associated clinicopatholoic features of
the mutation in )IP1&11P'G)RA in FB adults presentin $ith an a(solute eosinophil count of
hiher than 1:A > 10
B
?L: !ardanani and his team
@
used a fluorescence in situ hy(ridi9ationD(ased
stratey to identify )IP1&11P'G)RA in (one marro$ cells: #one of F patients $ith reactive
eosinophilia demonstrated defects in )IP1&11P'G)RA/ $hereas the rate of )IP1&11P'G)RA in
the remainin F1 patients $ith primary eosinophilia $as 1@H +11 patients,: #one +0H, of A7
patients $ith H/) (ut 10 +AEH, of 1B patients $ith systemic mast cell disease associated $ith
eosinophilia +)M*D0eos, carried the mutated )IP1&11P'G)RA: 2hus, it seems )IP1&11
P'G)RA is not solely responsi(le for H/): Ho$ever, a @0H partial response rate $as o(served
in 10 H/) cases after treatment $ith imatini(:
Mc!herson et al
A
reported a ;;0year0old man $ith recurrent papular s.in lesions and mar.ed
peripheral eosinophilia $hose s.in histopatholoy sho$ed a proliferation of *D;0
U
2 cells
consistent $ith lymphomatoid papulosis and in $hom molecular analysis of peripheral (lood
mononuclear cells demonstrated the presence of the )IP1&1:P'G)RA fusion ene:
Frequency
United #tate!
2he e3act incidence of H/) is hard to determine (ecause it is a dianosis of e3clusion: "t is a rare
condition, althouh numerous reports e3ist in the literature: At the #ational "nstitutes of Health
+#"H, (et$een 1B71 and 1BF2, A0 cases of H/) $ere dianosed and follo$ed up:
E
2he disease is
rare in children:
Internationa
H/) is rare, and the e3act incidence is uncertain:
Mortaity.Mor"idity
2he course of H/) varies from relatively indolent to fulminant and rapidly fatal: 2he pronosis
of H/) has improved sinificantly since definition of H/) and the development of imatini(:
Ultimately, the mortality associated $ith H/) id due to the occurrence of H/)0related
irreversi(le heart failure and the eventuality of malinant transformation of myeloid or lymphoid
cells into a fran. eosinophilic leu.emia:
2
)urvival statistics vary: A revie$ of A7 patients $ith advanced disease had a mean survival rate
of B months and a ;0year survival rate of 12H1 in another analysis of @0 patients, the A0year
survival rate $as F0H and the 100year survival rate $as @2H: A study from the #"H in 1BF2
E

noted a mean duration of disease of @:F years +rane, 102@ y,: Ho$ ne$er treatments, such as
cyclosporine, have affected mortality and mor(idity is unclear:
Race
#o racial predilection is reconi9ed:
#e/
Male predominance +@0B:1 ratio, has (een reported in historic series, (ut this is li.ely to reflect
the 8uasi0e3clusive male distri(ution of a sporadic hematopoietic stem cell mutation found in a
recently characteri9ed disease variant:
2
Age
A study from the #"H
E
of A0 patients reported that the mean ae of onset $as ;; years: "n 70H of
patients, the onset of disease occurs (et$een 200A0 years: Althouh rare, this disease H/) does
occur in children: A revie$ in 1BF7
7
from &ales found 1F pu(lished reports of H/) in children
youner than 1E years: 2he incidence seems to decrease in elderly persons:
)0INI)A0
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Hi!tory
H/) is a multisystem disease, and the presentin complaint can vary dependin on the oran
involved: 2he presentation can (e acute +e, stro.e,, as $hen cardiac and neuroloic systems are
involved, or, more commonly, H/) has an insidious onset: "n an #"H series
E
, common symptoms
included fatiue +2EH,, couh +2@H,, (reathlessness +1EH,, muscle pains or anioedema +1@H,,
and fever +12H,: )$eatin and pruritus are common: Mucocutaneous manifestations occur in 2A0
A0H of patients: /osinophilia $as incidentally detected in 12H of patients $ith H/): !atients
$ith H/) can have lo$0rade fevers: )ome patients $ith H/) e3perience alcohol intolerance
$ith a(dominal pain, flushin, nausea, $ea.ness, or diarrhea:
Mucocutaneous manifestations include the follo$in:

o *ommon manifestations
o
!ruritus
Urticaria
Dermatoraphism
Anioedema
/rythematous papules, pla8ues, and nodules
#onspecific rashes
o Uncommon manifestations
o
A8uaenic pruritus
F
)plinter hemorrhaes
!alpa(le purpura
Livedoid discoloration
&ells syndrome
B
Livedoid discoloration
/rythroderma
5esicular disease
/osinophilic vasculitis
Acral necrosis
10
!etechiae
/rythema annulare centrifuum
Mucosal ulceration and erythema
6ullous pemphioid +responded to imatini(,
11
*ardiac symptoms
12, 1;

o 2he heart is commonly involved, and throm(oem(olic complications resultin

from cardiac involvement can lead to multisystem disease:
o Heart damae evolves throuh ; staes: +1, an acute necrotic stae +$ith a mean
disease duration of A:A $.,, +2, a throm(otic stae +100mo mean duration of
eosinophilia,, and +;, a fi(rotic stae +after appro3imately 20y duration of
disease,:
o "n summary, H/) can result in endomyocardial fi(rosis, valvular disease and
lesions, mural throm(us formation, cardiomealy due to infiltration of the
myocardium $ith eosinophils, and pericardial effusion:
o )ymptoms are most common durin the throm(otic and fi(rotic phases and
include chest pain, dyspnea, and orthopnea:
#euroloic symptoms
1@

o 2hrom(oem(olic complications are usually from the heart and present as stro.es
or transient ischemic attac.s +2"As,:
o !rimary *#) dysfunction usually presents $ith symptoms of encephalopathy,
such as (ehavior chanes, confusion, (lurry vision, memory loss, ata3ia, and
upper motor neuron sins:
o !eripheral neuropathies present as symmetric or asymmetric sensory chanes,
pure motor deficits, mi3ed sensory and motor defects, or paresthesias: 2he cause
is poorly understood: !eripheral neuropathies cause A0H of all neuroloic
complications:
!ulmonary symptoms

o !ulmonary symptoms may result from *H4, pulmonary em(oli from the riht
side of the heart, or infiltration of the luns (y eosinophils:
o 2he most common symptom is a chronic, nonproductive couh: Dyspnea may
occur due to *H4 or pleural effusions +$hich are sometimes primarily caused (y
H/),: 6ronchospasm asthmatic symptoms can occur:
Hematoloic symptoms
1A

o #onspecific symptoms, such as fatiue due to anemia or easy (ruisin due to

throm(ocytopenia, can occur: /osinophils can cause vasculitis1 therefore,
vasculitis in different orans, includin the s.in, can (e associated $ith H/):
)ome cases evolve into eosinophilic leu.emia or other forms of leu.emia:
o 2hrom(otic episodes often occur and present $ith neuroloic complications: 2he
throm(otic events may occur secondary to heart dysfunction, or they may (e
caused (y hypercoaula(ility: 2he mechanism of hypercoaula(ility remains to (e
fully defined:
7" symptoms

o 7" involvement can occur secondary to em(olic disease from the heart or from
eosinophil infiltration of the 7" tract, the liver, or the spleen:
o )plenomealy presents $ith left upper 8uadrant pain and occurs in a(out @0H of
patients:
o Diarrhea occurs in 20H of patients:
o A(dominal pain, vomitin, and nausea can occur: 2he stomach may (ecome
dilated:
o Liver and all (ladder dysfunction and ascites can also result: A report has noted
H/) and sclerosin cholanitis: "n such cases, the symptoms and (lood
parameters of liver dysfunction can (e associated $ith eosinophilia and hih
serum "/ levels: Durin corticosteroid therapy, these parameters improve, and
morpholoic improvements of the (ile ducts can also usually (e o(served: 2he
pathoenesis of sclerosin cholanitis may (e e3plained, in part, (y the concept of
H/) or alleric reaction:
o Ulcers, hepatitis, astritis, colitis, pancreatitis, 6udd0*hiari syndrome, and
cholanitis can occur:
o &atana(e et al
1E
reported a E@0year0old man $ith H/): 2his patient had from
dysphaia, s$ellin of the oral mucosa and the posterior cervical muscles,
a(dominal pain, and diarrhea: 2his elderly man had an a(normal num(er of
eosinophils in his (lood: *2 scannin revealed thic.enin of the posterior $all of
the pharyn3, esophaus, and 7" tract: A lo$er lip tissue specimen demonstrated a
moderate infiltration of eosinophils:
'heumatoloic symptoms: Arthralia, arthritis, 'aynaud phenomenon, and &ells
syndrome have (een reported $ith H/):
=cular symptoms

o 5isual symptoms, especially (lurrin, can occur:

o Adie syndrome +pupillotonia,, .eratocon<unctivitis, and episcleritis can occur:
o 'etinal and (lood vessel a(normalities can occur, more often as a result of
microthrom(i than arteritis:
*onstitutional symptoms

o Many patients e3perience fever and niht s$eats:

o Anore3ia and $eiht loss are uncommon presentin symptoms1 these symptoms
are often related to an underlyin cardiac disease:
=liospermia has (een reported in a patient receivin imatini( therapy for the H/):
&hy!ica
2he sins and symptoms are dependent on the oran system involved:
Mucocutaneous sins

o Urticarial $heals and anioedema are common:

o Dermatoraphism occurs in as many as 7AH of patients:
o /rythematous, pruritic papules and pla8ues are the other ma<or dermatoloic
manifestation:
o 6listerin lesions and necrotic ulcers secondary to dermal microthrom(i have
(een reported:
o !etechiae, enerali9ed erythroderma, erythema annulare centrifuum, and
'aynaud phenomenon are other cutaneous manifestations:
o )plinter hemorrhaes can result from cardiac throm(oem(oli:
o Ulcers can occur on virtually any mucosal surface:
*ardiac sins

o )ins of heart disease vary dependin on the stae of involvement, and they
(ecome more prominent in the latter staes of the disease:
o )plinter hemorrhaes, arrhythmias, murmurs +particularly mitral and tricuspid
reuritation,, restrictive cardiomyopathy, cardiomealy, as $ell as other *H4
manifestations all occur and have a $orse pronosis: 2he symptoms of H/) can
resem(le restrictive cardiac disease:
#euroloic sins

o Acute neuroloic deficits are usually the result of throm(oem(olic disease:

o !rimary *#) involvement manifests as chanes in mental status, ata3ia, increased
deep muscle tone, increased deep tendon refle3es, and a positive 6a(ins.i sin:
)ei9ures can occur (ut are less common:
o &hen peripheral nerves are involved, patients e3hi(it sensory and?or motor
deficits: 'adiculopathies, muscle atrophy from denervation, and mononeuritis
multiple3 have (een reported: 7enerali9ed $ea.ness has (een noted (ut is not a
dianostic sin of H/):
!ulmonary sins

o !leural effusions are common as a result of *H4:

o Diffuse or focal crac.les may (e appreciated as a result of pulmonary infiltration
(y eosinophils or (y ensuin pulmonary fi(rosis:
o !leuritic chest pain and hypo3ia can (e caused (y pulmonary em(oli oriinatin
from the riht side of the heart:
7" sins

o 6ecause H/) can affect every a(dominal oran, complaints of a(dominal pain
need to (e immediately evaluated:
o 6o$el necrosis, $ith the classic Vpain out of proportion to e3amination,V due to
throm(oem(olic disease is life threatenin:
o )plenomealy is common:
'heumatoloic sins

o %oint effusions can occur:

o 2he characteristic color chanes of 'aynaud phenomenon may (e o(served:
=cular sins: =ccasional visual (lurrin may occur:
)au!e!
H/) is a clonal proliferation of eosinophils: 6y definition, H/) is an idiopathic condition:
)ome have speculated that H/) is not primarily a disease of eosinophils (ut rather a
disease of 2 cells that secrete cyto.ines that result in such clonal proliferations: )uch
clonal eosinophils are activated and have more eosinophilic mediators than normal
eosinophils:
)ome cases of H/) turn into leu.emia, and, as such, chromosomal a(normalities are at
the root of some cases of H/): A study from the #"H
E
found chromosomal a(normalities
in F of ;; patients e3amined: )uch a(normalities can include the !hiladelphia
chromosome:
DIFFERENTIA0#
)ection @ of 11
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Differentials
&or.up
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4ollo$0up
Miscellaneous
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'eferences
Aniolymphoid Hyperplasia $ith /osinophilia
*hur0)trauss )yndrome +Alleric 7ranulomatosis,
/osinophilia0Myalia )yndrome
/osinophilic 4asciitis
/osinophilic !ustular 4olliculitis
/osinophilic Ulcer
Gimura Disease
)tronyloidiasis
&ells )yndrome +/osinophilic *ellulitis,
Other &ro"em! to "e )on!idered
/osinophilic leu.emia
Leu.emia
Dru reactions
/osinophilic to3ocariasis
/pisodic anioedema $ith eosinophilia
Hypersensitivity diseases
!arasitic infections
WORKU&
)ection A of 11
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2reatment
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4ollo$0up
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'eferences
0a" #tudie!
Hematoloy

o 2he eosinophil count is reater than 1:A > 10

B
?L: /osinophils can e3hi(it
structural a(normalities, such as cytoplasmic vacuoli9ation and nuclear
hypersementation: =n a peripheral smear, eosinophils may (e normal in
appearance, (ut often some morpholoic a(normalities, such as a decrease in
ranule num(er and si9e, are o(served:
o #eutrophilia is common, (ut (andemia is infre8uent: /3tremely hih leu.ocyte
counts and immature forms may indicate a leu.emia and have a $orse pronosis:
o Leu.ocyte al.aline phosphatase levels can (e elevated or decreased:
o =f patients $ith H/), A0H have anemia: 2eardrop cells and nucleated
erythrocytes can often (e found on a peripheral smear:
o 2hrom(ocytopenia is seen in ;1H of patients1 ho$ever, 1EH of patients have an
elevated platelet count:
o 2he erythrocyte sedimentation rate may (e elevated:
5itamin levels

o 5itamin 6012 and vitamin 6012D(indin protein levels may (e elevated:

17
o 4olate levels can (e (elo$ the reference rane:
!leural fluid: 2his analysis typically reveals a transudate1 ho$ever, e3udative effusions
containin eosinophils can (e present:
*hromosome analysis

o *hromosomal a(normalities are diverse, $ith the most common (ein

aneuploidy:
o 2he !hiladelphia chromosome has occasionally (een found:
o *lonality of eosinophils has (een o(served:
"mmunolo(ulins levels: Hih immunolo(ulin / +"/, levels are found in ;FH of
patients: /levations in immunolo(ulin 7 +"7,, immunolo(ulin A +"A,, and
immunolo(ulin M +"M, levels are less common:
Urine analysis: !roteinuria, hematuria, al(uminuria, and?or hyaline casts may (e present:
6lood chemistry analysis: 'enal and liver function test values can (e elevated:
Imaging #tudie!
*ardiac studies

o /chocardioraphy can (e used to assess throm(us formation, fi(rosis, pump

function, and valvular dysfunction: Mitral and tricuspid dysfunction may also (e
detected:
o /*7 often reveals 20$ave inversion and can (e used to evaluate arrhythmias:
o *ardiac catheteri9ation and anioraphy can (e used to evaluate myocardial
function and valvular dysfunction:
!ulmonary studies: *hest radioraphy and *2 can demonstrate pleural effusions,
pulmonary infiltrates and fi(rosis, and cardiomealy:
#euroloic studies

o Head *2 and M'" can reveal stro.es1 2"As1 and increased cere(rospinal fluid
+*)4, pressure, particularly from inflammation of central nerve tissue:
o !eripheral nerve conduction studies are useful in assessin neuropathies:
7" studies

o A(dominal *2 can (e used to evaluate hepatosplenomealy, the hepatic vein

+6udd0*hiari syndrome,, and intestinal infarction:
o Anioraphy can (e used to assess the mesenteric vascular supply $hen em(olic
disease is suspected:
o /ndoscopy and (arium studies can (e used to evaluate ulcerations:
&rocedure!
/ndocardial (iopsy can help in dianosin H/), particularly early in the disease $hen
other cardiac sins and symptoms are not yet present: 'iht ventricular (iopsy can (e
performed to evaluate for endomyocardial involvement:
!leural fluid aspiration should (e performed in patients $ith an effusion:
6one marro$ aspiration and (iopsy, $ith evaluation of cytoenetics, can reveal
myelofi(rosis or a leu.emia:
6ecause cutaneous lesions are nonspecific, s.in (iopsy may (e necessary to confirm the
dianosis and to rule out other causes:
4luorescein anioraphy may (e performed even if patients do not have ocular
symptoms: 4luorescein anioraphy has demonstrated that more than A0H of patients
$ith H/) have choroidal a(normalities, includin patchy and delayed fillin, and retinal
vessel a(normalities:
Hi!toogic Finding!
2he histopatholoic findins vary: )everal reports have noted microthrom(i in (lood vessels
alon $ith a varia(le superficial, deep, and interstitial perivascular infiltrate of eosinophils and
other inflammatory cells: =ne report descri(in ; patients lin.ed an eosinophilic vasculitis to a
recurrent purpuric rash: "n a patient $ith multiple indurated pla8ues, a dermal infiltrate $ith
eosinophils $ith flame fiures $as found: "n eosinophilia $ith recurrent anioedema, a clinical
syndrome thouht to (e a variant of H/), the infiltrate is primarily mononuclear $ith fe$
eosinophils:
6iopsy samples of mucosal ulcerations typically demonstrate a mi3ed cell infiltrate $ithout
vasculitis:
/ndocardial (iopsy findins vary dependin on the stae of the disease: "n early disease,
eosinophil infiltration $ith eosinophil microa(scesses and myocardial necrosis are found: "n
advanced disease, fi(rosis predominates:
"n patients $ith neuropathy, peripheral nerve (iopsy samples usually sho$ a3onal loss and no
evidence of vasculitis or eosinophil infiltration:
TREATMENT
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Medica )are
4or 4"!1L10!D74'A fusion ene patients, imatini( is first line therapy:
1F
"matini(Ks adverse
effects and e3pense $arrant consideration (efore usin it: )pecifically, imatini(, $hich (loc.s
the effects of platelet0derived ro$th factor, has transformed the care of a lare su(set of patients
$ith H/) and can (e helpful: "t can lead to a sustained drop in the eosinophil count: Ho$ever,
(ecause the causes of H/) are varia(le, some patients miht need other therapies:
!atients $ith increased "L0A production due to clonally e3panded 20cell population +lymphocytic
variant, initially receive corticosteroids, follo$ed (y aents includin hydro3ycar(amide,
interferon0alfa, and imatini(: Mepoli9uma(, an anti0"L0A anti(ody, may (e an effective
corticosteroid0sparin aent for patients $ith lymphocytic H/):
2
2he oal of therapy is to control oran damae, $hich, in many cases, especially those involvin
the heart, does not correlate $ith the level of hypereosinophilia: 2hus, no therapy is necessary in
asymptomatic disease $ithout any evidence of oran damae: Ho$ever, (ecause cardiac damae
can develop insidiously, patients need close clinical and echocardioraphic follo$0up care:
!reviously, corticosteroids $ere the first line of therapy for H/): &ith the development
of imatini(, $hile corticosteroids miht (e the optimal initial therapy, imatini( can (e
seen as the most potent and dura(le treatment for H/): 2he steroids should rapidly
+usually $ithin @ h, decrease the eosinophil count: "f steroids fail to reduce the eosinophil
count, they may (e discontinued: +)ome patients have symptomatic improvement $ithout
chanes in eosinophil counts:, !atients $ho respond to steroids +usually those $ith
urticaria?anioedema and hih "/ levels, usually have a ood pronosis: A short trial of
corticosteroids in patients $ho are asymptomatic may help predict the future response to
therapy:
*hemotherapeutic aents +ie, hydro3yurea, vincristine, etoposide M5!1E021;N,
chloram(ucil, have (een used $ith varia(le success in patients $hose conditions $ere
unresponsive to steroids:
/3perimental treatment $ith antiD"L0A anti(ody )*HAA700 and alemtu9uma( has (een
reported to (e effective: 6ioloic response modifiers, such as interferon alfa and
cyclosporine, have (een used:
"n 2007, 2averna et al
1B
noted that infli3ima( is a therapy for idiopathic H/):
Leu.apheresis is sometimes used: "t removes eosinophils from the (lood: Leu.apheresis
results in short0lived reductions in eosinophil counts and is larely unsuccessful as a
therapy modality: "t can (e used in emerency situations in patients $ith e3tremely hih
eosinophil counts:
Anticoaulants and antiplatelet aents are used in patients $ith evidence of throm(osis or
throm(oem(olism (ecause throm(oem(olic manifestations are often a part of H/) and
cause many of its $orst symptoms: #o data e3ist that sho$ $hether anticoaulation
treatment has any (enefit: 2he effectiveness of anticoaulation treatment is anecdotal
(ecause some patients continue to have throm(otic complications despite therapy: Many
patients still form clots despite anticoaulation therapy:
!hototherapy $ith psoralen and U50A +!U5A,, dapsone +papulonodular lesions,, and
sodium chromolycate have (een used $ith anecdotal success for patients $ith pruritus:
#arro$ (and U506 phototherapy miht (e effective as $ell, (ut its use has not (een
descri(ed:
Antihistamines can (e used, (ut they are only add0on therapies and not primary
treatments: Antihistamines that have a ood effect include cetiri9ine, hydro3y9ine, and
do3epin: 6ecause do3epin can affect the heart, it should (e used $ith caution in patients
$ith H/): )edatin antihistamines, such as hydro3y9ine and do3epin, can provide
symptomatic relief:
*omplications, such as *H4, should (e treated aressively:
6one marro$ transplantation after chemotherapy has rarely (een used in severe cases of
H/), (ut, (ecause of the mor(idity involved $ith this treatment, it should (e used
sparinly:
Lon0term remission of H/) has (een reported follo$in alloeneic stem cell
transplantation in spite of transient eosinophilia posttransplant:
#urgica )are
)plenectomy can reduce the pain due to splenic enlarement and is also (eneficial in
cases of throm(ocytopenia secondary to hypersplenism: Ho$ever, leu.ocyte and
eosinophil counts can increase follo$in splenectomy:
*ardiac surery for annuloplasty, throm(ectomy, and valve replacement has a definite
role in treatin heart disease due to H/): 6ioprosthetic valves should (e used (ecause
mechanical valves are more prone to throm(osis:
'arely, in neuroloic dysfunction, underlyin edema of the (rain and an increase in *)4
pressure may (e present: "f these result, the patient must immediately undero surery (y
a neurosureon to insert a shunt or other means for normali9in *)4 pressure to prevent
herniation:
)on!utation!
H/) is a multisystem disorder: "t is often hard to dianosis (ecause its symptoms are not
specific: *onsultation from all medical specialties can (e helpful in ma.in the dianosis: "n
particular, consultation $ith a cardioloist, a hematoloist, and a dermatoloist can (e helpful:
MEDI)ATION
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'eferences
2herapy is eared to$ard reducin oran damae: *orticosteroids are the initial drus of choice,
and prednisone produces a response in appro3imately EEH of patients: A response to prednisone
manifests as a reduction in the eosinophil count $ithin @F hours: Usually, the response is more
rapid:
"matini(, $hich (loc.s the effects of platelet0derived ro$th factor, has transformed the care of a
lare su(set of patients $ith H/) and can (e helpful: "t can lead to a sustained drop in the
eosinophil count: Ho$ever, (ecause the causes of H/) are varia(le, predictin the
responsiveness of a patient to imatini( mesylate therapy remains difficult:
4or conditions unresponsive to prednisone, chemotherapeutic and (ioloic aents can (e used:
2he to3icity of these aents should al$ays (e considered, and the ris.0(enefit ratio of these
treatments must (e assessed:
Drug )ategory+ Corticosteroids
2hese aents rapidly suppress peripheral eosinophil counts: 2hey have anti0inflammatory
properties and cause profound and varied meta(olic effects: *orticosteroids modify the (odyKs
immune response to diverse stimuli:
Drug Name
!rednisone +Deltasone, Meticorten, =rasone,
)terapred,
De!cri-tion
"mmunosuppressant for treatment of autoimmune
disorders1 may decrease inflammation (y reversin
increased capillary permea(ility and suppressin
!M# activity: )ta(ili9es lysosomal mem(ranes and
suppresses lymphocyte and anti(ody production:
Adut Do!e
E0 m?d !=1 eventually taper or chane to
alternate0day reimen
&ediatric Do!e
1 m?. != 8d1 eventually taper or chane to
alternate0day reimen
)ontraindication!
Documented hypersensitivity1 active infection1
ocular herpes simple31 chic.enpo3, measles, or
live virus e3posure
Interaction! *oadministration $ith estroens may decrease
clearance1 concurrent use $ith dio3in may cause
diitalis to3icity secondary to hypo.alemia1
pheno(ar(ital, phenytoin, and rifampin may
increase lucocorticoid meta(olism +consider
increasin maintenance dose,1 monitor for
hypo.alemia $ith coadministration of diuretics
&regnancy
6 0 4etal ris. not confirmed in studies in humans
(ut has (een sho$n in some studies in animals
&recaution!
May mas. infections1 a(rupt discontinuation of
lucocorticoids $hen used J 2 $. may cause
adrenal crisis1 may cause hyperlycemia, edema,
osteonecrosis, myopathy, peptic ulcer disease,
hypo.alemia, osteoporosis, euphoria, psychosis,
myasthenia ravis, ro$th suppression, and
infections
Drug )ategory+ Antineoplastics
2hese aents interfere $ith cell division, thus reducin eosinophil production: 2hey are
particularly to3ic to rapidly dividin cells:
Drug Name Hydro3yurea +Hydrea,
De!cri-tion
"nterferes $ith D#A synthesis: Used to reduce
total leu.ocyte count to I10,000?L: 'e8uires 701@
d for effectiveness:
Adut Do!e
10; ?d !=, continued as lon as no sinificant
reduction in platelet count occurs
&ediatric Do!e 200;0 m?.?d !=
)ontraindication!
Documented hypersensitivity1 (one marro$
depression, leu.openia I2A00?L, or
throm(ocytopenia I100,000?L1 pancreatitis
Interaction!
!otentiates pancreatitis $ith antiretroviral
medications1 coadministration $ith fluorouracil
can increase neuroto3icity
&regnancy
D 0 4etal ris. sho$n in humans1 use only if
(enefits out$eih ris. to fetus
&recaution!
*losely monitor (lood counts at least $ee.ly1
severe anemia re8uires resolution (efore initiatin
therapy1 renal failure re8uires dose ad<ustment1
erythema occurs if individual has received
radiation therapy in past1 produces anemia +$hich
often re8uires (lood transfusion, and
throm(ocytopenia +$hich occasionally re8uires
platelet transfusion,
Drug Name 5incristine +=ncovin, 5incasar,
De!cri-tion "nhi(its cellular mitosis (y inhi(ition of
intracellular tu(ulin function, (indin to
microtu(ule and spindle proteins in the ) phase:
Used to reduce total leu.ocyte count to
I10,000?L: /ffective in 10; d and spares (one
marro$ to3icity (ut may cause paresthesias:
Adut Do!e 1:A02 m "5 as a sinle dose at 20$. intervals
&ediatric Do!e
I10 .: 0:0A m?. "5
J10 .: 1:A02 m?m
2
"5
#ot to e3ceed 2 m?dose
)ontraindication!
Documented hypersensitivity1 "2 administration
may cause death
Interaction!
Acute pulmonary reaction may occur $hen ta.en
concurrently $ith mitomycin0*1 asparainase,
*-!@A0 ;A@ inhi(itors +e, itracona9ole,
8uinupristin?dalfopristin, sertraline, ritonavir,,
7M0*)4 +e, sarramostim, filrastim,, or
nifedipine increase to3icity1 *-!@A0 ;A@ inducers
+e, car(ama9epine, phenytoin, pheno(ar(ital,
rifampin, may decrease effects
&regnancy
D 0 4etal ris. sho$n in humans1 use only if
(enefits out$eih ris. to fetus
&recaution!
*aution in severe cardiopulmonary disease or
pree3istin neuromuscular dysfunction1 ensure
intact vascular access (ecause e3travasation
produces severe tissue damae +if severe tissue
damae occurs, in<ection of hyaluronidase and
application of heat help disperse dru and reduce
damae,1 do not in<ect directly (ut only throuh "5
access line esta(lished as nonlea.in1 o(tain (lood
count (efore each dose1 does not cross (lood0(rain
(arrier, (ut do not administer intrathecally1 avoid
eye contamination1 hydrate patient to avoid uric
acid nephropathy +if uric acid elevations are
severe, consider allopurinol prophyla3is,1 if
(iliru(in levels are J ; m?dL, reduce dose (y
A0H1 may cause paresthesias
Drug Name *hloram(ucil +Leu.eran,
De!cri-tion
Al.ylates and cross0lin.s strands of D#A,
inhi(itin D#A replication and '#A transcription:
Used to reduce total leu.ocyte count to
I10,000?L:
Adut Do!e
@010 m?m
2
!= for @ consecutive days every other
mo
&ediatric Do!e
0:100:2 m?.?d !=1 use for minimal time (ecause
of ris. of secondary malinancies
)ontraindication!
Documented hypersensitivity1 previous resistance
to medication1 (lood dyscrasias1
throm(ocytopenia1 leu.openia1 severe anemia
Interaction! #one reported
&regnancy
D 0 4etal ris. sho$n in humans1 use only if
(enefits out$eih ris. to fetus
&recaution!
'e8uires $ee.ly (lood counts1 may cause
chromosome damae and sterility1 do not
administer $ithin @ $. of radiation therapy1
induces secondary malinancies1 caution in history
of sei9ure disorders or current (one marro$
suppression1 total doses JE:A m?. increase ris.
of irreversi(le (one marro$ damae
Drug )ategory+ Immunomodulators
/mpirically applied to many diseases as immunomodulator:
Drug Name "nterferon alfa 2a and 2( +"ntron A, 'oferon,
De!cri-tion
'eported to reduce eosinophil counts in some
patients:
Adut Do!e
F million U?d "M?)* initially, then 2 million U?d
or A07 million U ; times?$.
&ediatric Do!e
#ot esta(lished1 consider 2:A0A million U?m
2
?d
"M?)*1 deaths reported $ith doses of ;0 million
U?m
2
?d
)ontraindication! Documented hypersensitivity
Interaction! 'educes theophylline clearance
&regnancy
* 0 4etal ris. revealed in studies in animals (ut not
esta(lished or not studied in humans1 may use if
(enefits out$eih ris. to fetus
&recaution!
Assess (lood counts (efore therapy1 chec.
preservative and (ioloic source to ensure patient
is not alleric1 (rands not interchanea(le1 patient
should avoid tas.s re8uirin mental alertness after
hih0dose therapy1 $arn patient that depression
and suicidal ideation are adverse effects1 can cause
fluli.e symptoms1 caution in severe hepatic or
renal insufficiencies, sei9ure disorders, multiple
sclerosis, or compromised *#)
Drug )ategory+ Immunosuppressants
2hese aents inhi(it .ey factors in the immune system that are responsi(le for immune reactions:
Drug Name *yclosporine +#eoral, )andimmune,
De!cri-tion
*yclic polypeptide that suppresses some humoral
immunity and, to a reater e3tent, cell0mediated
immune reactions: #ot approved for this use: May
(e com(ined $ith prednisone:
Adut Do!e 2:A0A m?.?d != in divided doses
&ediatric Do!e Administer as in adults
)ontraindication!
Documented hypersensitivity1 uncontrolled
hypertension or malinancies1 do not administer
concomitantly $ith !U5A or U506 radiation in
psoriasis (ecause it may increase ris. of cancer
Interaction!
*ar(ama9epine, phenytoin, isonia9id, rifampin,
and pheno(ar(ital may decrease cyclosporine
concentrations1 a9ithromycin, itracona9ole,
nicardipine, .etocona9ole, flucona9ole,
erythromycin, verapamil, rapefruit <uice,
diltia9em, aminolycosides, acyclovir,
amphotericin 6, and clarithromycin may increase
to3icity1 acute renal failure, rha(domyolysis,
myositis, and myalias increase $hen ta.en
concurrently $ith lovastatin1 methylprednisolone
and cyclosporine mutually inhi(it one another,
resultin in increased plasma levels of each dru
&regnancy
* 0 4etal ris. revealed in studies in animals (ut not
esta(lished or not studied in humans1 may use if
(enefits out$eih ris. to fetus
&recaution!
/valuate renal and liver functions often (y
measurin levels of 6U#, serum creatinine, serum
(iliru(in, and liver en9ymes1 may increase ris. of
infection and lymphoma1 reserve "5 use only for
those $ho cannot ta.e !=
Drug Name "matini( mesylate +7leevec,
De!cri-tion )pecifically desined to inhi(it tyrosine .inase
activity of the (cr0a(l .inase in !hU leu.emic
*ML cell lines: Used to treat *ML in (last crisis,
accelerated phase, or in chronic phase after failure
to interferon alfa therapy: &ell a(sor(ed after oral
administration, $ith ma3imum concentrations
achieved $ithin 20@ h: /limination is primarily in
feces in form of meta(olites:
Adut Do!e
*hronic phase: @00 m != 8d $ith food1 may
increase to E00 m?d in a(sence of adverse effects
Accelerated phase or (last crisis: E00 m != 8d
$ith food1 may increase to F00 m?d divided (id in
a(sence of adverse effects
&ediatric Do!e #ot esta(lished
)ontraindication! Documented hypersensitivity
Interaction!
*-!;A@ inhi(itors +.etocona9ole, increase
distri(ution1 *-!;A@ su(strates +simvastatin,
increase ma3imum concentration (y 20;:A0fold1
*-!;A@ inducers +phenytoin, decrease AU* (y
appro3imately one fifth of typical AU*1 li.ely to
increase (lood levels of drus that are su(strates of
*-!2*B, *-!2DE, and *-!;A@?A
&regnancy
D 0 4etal ris. sho$n in humans1 use only if
(enefits out$eih ris. to fetus
&recaution!
'educe dose if edema or anemia occurs,
transaminases or (iliru(in (ecomes elevated, or
rade ;0@ neutropenia or throm(ocytopenia
develops
FO00OW1U&
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Further In-atient )are
!rompt hospitali9ation and treatment of disease and therapy complications are essential:
Further Out-atient )are
*areful clinical, la(oratory, and imain follo$0up care is necessary to ensure that ne$
disease symptoms and sins are identified and that appropriate therapy is promptly
instituted:
Multidisciplinary interaction (et$een a hematoloist, a dermatoloist, a cardioloist, a
sureon, and other su(specialists should (e readily availa(le $hen necessary:
!atients can have $a3in and $anin disease1 thus, lon0term treatment of this condition
miht (e necessary:
In.Out &atient Med!
"f H/) does not remit, it must (e treated $ith prednisone or other immunosuppressive
drus:
Tran!3er
"f the patient has e3perienced cardiac or other systemic collapse, the patient must (e
transferred to the "*U: 6ecause H/) is usually a slo$ly proressin disease, transfer is
not often necessary:
Deterrence.&re7ention
At this time, no prevention of H/) is .no$n:
)om-ication!
6ecause H/) is a multisystem disease, the complications depend on the orans involved:

o *ardiac involvement leadin to *H4 and death is the most feared complication:
o 2hree types of neuroloic complications occur: throm(oem(olic, primary *#)
dysfunction, and peripheral neuropathies +see !hysical,:
&rogno!i!
7ood pronostic factors include the follo$in:

o 7ood response to prednisone

o Urticaria?anioedema lesions as the type of s.in involvement
o A(sence of symptoms, particularly *H4
!oor pronostic factors include the follo$in:

o Anemia
o 2hrom(ocytopenia
o &6* count reater than B0 > 10
B
?L
o A(normal circulatin cells
o A(normal (one marro$
o A(normal leu.ocyte al.aline phosphatase levels
o *hromosomal a(normalities +e, !hiladelphia chromosome, suestive of a
myeloproliferative disorder
o /arly aressive oran involvement +especially *H4,
&atient Education
"nstruct patients a(out the potential symptoms and the importance of rapid intervention:
MI#)E00ANEOU#
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Medica.0ega &it3a!
4ailure to dianosis H/), $hich is a dianosis of e3clusion, is a pitfall:

o 4ailure to dianosis this condition can lead to irreversi(le cardiac damae:

o 6ecause H/) is a dianosis of e3clusion, a full dianostic $or.up must (e
completed to e3clude other causes of eosinophilia and systemic symptoms:
o =ne must remem(er that H/) can result in throm(osis and vasculitis and that
these conditions must (e reconi9ed and treated:
MU0TIMEDIA
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Media file 1: Urticaria and erythematou! ra!h4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 2: &etechiae on an erythematou! "a!e4
5ie$ 4ull )i9e "mae
Media type: !hoto
REFEREN)E#
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1: *husid M%, Dale D*, &est 6*, &olff )M: 2he hypereosinophilic syndrome: analysis of
fourteen cases $ith revie$ of the literature: e!icine "#altimore$: %an 1B7A1A@+1,:10
27: MMedlineN:
2: 'oufosse 4/, 7oldman M, *oan /: Hypereosinophilic syndromes: *rphanet J Rare
'is: )ep 11 200712:;7: MMedlineN:
;: )imon HU, !lCt9 )7, Dummer ', 6laser G: A(normal clones of 2 cells producin
interleu.in0A in idiopathic eosinophilia: N Engl J e!: =ct 7 1BBB1;@1+1A,:11120
20: MMedlineN:
@: !ardanani A, 6roc.man )', !aternoster )4, 4lynn H*, Getterlin '!, Lasho 2L, et
al: 4"!1L10!D74'A fusion: prevalence and clinicopatholoic correlates in FB
consecutive patients $ith moderate to severe eosinophilia: #loo!: #ov
1A 200@110@+10,:;0;F0@A: MMedlineN:
A: Mc!herson 2, *o$en /&, Mc6urney /, Glion AD: !latelet0derived ro$th factor
receptor0alpha0associated hypereosinophilic syndrome and lymphomatoid papulosis: #r J
'ermatol: =ct 200E11AA+@,:F2@0E: MMedlineN:
E: 4auci A), Harley %6, 'o(erts &*, 4errans 5%, 7ralnic. H', 6<ornson 6H: #"H
conference: 2he idiopathic hypereosinophilic syndrome: *linical, pathophysioloic, and
therapeutic considerations: Ann Intern e!: %ul 1BF21B7+1,:7F0B2: MMedlineN:
7: Alfaham MA, 4eruson )D, )ihra 6, Davies %: 2he idiopathic hypereosinophilic
syndrome: Arch 'is Chil!: %un 1BF71E2+E,:E0101;: MMedlineN:
F: #e$ton %A, )inh AG, 7reaves M&, )pry *%: A8uaenic pruritus associated $ith the
idiopathic hypereosinophilic syndrome: #r J 'ermatol: %an 1BB01122+1,:10;0
E: MMedlineN:
B: 6oenrieder 2, 7riese D!, )chiffner ', 6Lttner ', 'ieer 7A, Hohenleutner U, et
al: &ellsK syndrome associated $ith idiopathic hypereosinophilic syndrome: #r J
'ermatol: Dec 1BB711;7+E,:B7F0F2: MMedlineN:
10: 2a.e.a$a M, "mai G, Adachi M, Ao.i ), Maeda G, Hinoda -, et al: Hypereosinophilic
syndrome accompanied $ith necrosis of finer tips: Intern e!: #ov 1BB21;1+11,:12E20
E: MMedlineN:
11: Hofmann )*, 2echnau G, MLller AM, LL((ert M, 6ruc.ner02uderman L: 6ullous
pemphioid associated $ith hypereosinophilic syndrome: simultaneous response to
imatini(: J Am Aca! 'ermatol: May 20071AE+A )uppl,:)EF072: MMedlineN:
12: 6roc.inton "4, =lsen /7: LofflerKs endocarditis and Davies endomyocardial
fi(rosis: Am Heart J: 1B7;1FA:;0F:
1;: Davies %, )pry *%, )apsford ', =lsen /7, de !ere9 7, =a.ley *M, et al: *ardiovascular
features of 11 patients $ith eosinophilic endomyocardial disease: ; J
e!: 1BF;1A2+20A,:2;0;B: MMedlineN:
1@: Moore !M, Harley %6, 4auci A): #euroloic dysfunction in the idiopathic
hypereosinophilic syndrome: Ann Intern e!: %an 1BFA1102+1,:10B01@: MMedlineN:
1A: 4laum MA, )chooley '2, 4auci A), 7ralnic. H': A clinicopatholoic correlation of the
idiopathic hypereosinophilic syndrome: ": Hematoloic
manifestations: #loo!: #ov 1BF11AF+A,:1012020: MMedlineN:
1E: &atana(e M, Matsui #, Hamada ), =huchi %, )himohashi #, Gatoh M, et al: A rare case
of idiopathic hypereosinophilic syndrome involvin the oral cavity associated $ith the
esophaus and astrointestinal tract: Intern e!: Apr 200@1@;+@,:;;E0B: MMedlineN:
17: Oittoun %, 4arcet %!, Mar8uet %, )ultan *, Oittoun ': *o(alamin +vitamin 612, and 612
(indin proteins in hypereosinophilic syndromes and secondary
eosinophilia: #loo!: Apr 1BF@1E;+@,:77B0F;: MMedlineN:
1F: )cheinfeld #: A comprehensive revie$ of imatini( mesylate +7leevec, for
dermatoloical diseases: J 'rugs 'ermatol: 4e( 200E1A+2,:117022: MMedlineN:
1B: 2averna %A, Lerner A, 7old(er L, &erth ), Demierre M4: "nfli3ima( as a therapy for
idiopathic hypereosinophilic syndrome: Arch 'ermatol: )ep 200711@;+B,:11100
2: MMedlineN:
20: 6arna M, GemPny L, Do(o9y A: ).in lesions as the only manifestation of the
hypereosinophilic syndrome: #r J 'ermatol: Apr 1BB711;E+@,:E@E07: MMedlineN:
21: 6rito06a(apulle 4: *lonal eosinophilic disorders and the hypereosinophilic
syndrome: #loo! Re%: )ep 1BB7111+;,:12B0@A: MMedlineN:
22: *hun G4, He$ M, )core %, %ones A5, 'eiter A, *ross #*, et al: *ouh and
hypereosinophilia due to 4"!1L10!D74'A fusion ene $ith tyrosine .inase activity: Eur
Respir J: %an 200E127+1,:2;002: MMedlineN:
2;: *outrP ), 7otli( %: 2areted treatment of hypereosinophilic syndromes and chronic
eosinophilic leu.emias $ith imatini( mesylate: Semin Cancer #iol: Au 200@11@+@,:;070
1A: MMedlineN:
2@: Gat9 H2, Ha8ue )%, Hsieh 4H: !ediatric hypereosinophilic syndrome +H/), differs from
adult H/): J Pe!iatr: %an 200A11@E+1,:1;@0E: MMedlineN:
2A: Ga9miero$s.i %A, *husid M%, !arrillo %/, 4auci A), &olff )M: Dermatoloic
manifestations of the hypereosinophilic syndrome: Arch 'ermatol: Apr 1B7F111@+@,:A;10
A: MMedlineN:
2E: Leiferman GM, 7leich 7%, !eters M): Dermatoloic manifestations of the
hypereosinophilic syndromes: Immunol Allergy Clin North Am: Au 2007127+;,:@1A0
@1: MMedlineN:
27: Marshall 7M, &hite L: /ffective therapy for a severe case of the idiopathic
hypereosinophilic syndrome: Am J Pe!iatr Hematol *ncol: 1BFB111+2,:17F0
F;: MMedlineN:
2F: !arrillo %/, 4auci A), &olff )M: 2herapy of the hypereosinophilic syndrome: Ann Intern
e!: Au 1B7F1FB+2,:1E7072: MMedlineN:
2B: 'auch A/, Amyot GM, Dunn H7, # 6, &ilner 7: Hypereosinophilic syndrome and
myocardial infarction in a 1A0year0old: Pe!iatr Pathol &ab e!: May0
%un 1BB7117+;,:@EB0FE: MMedlineN:
;0: )ade G, Mysels A, Levo -, Givity ): /osinophilia: A study of 100 hospitali9ed
patients: Eur J Intern e!: May 200711F+;,:1BE0201: MMedlineN:
;1: )hei.h %, &eller !4: *linical overvie$ of hypereosinophilic syndromes: Immunol Allergy
Clin North Am: Au 2007127+;,:;;;0AA: MMedlineN:
;2: )Wnche9 %L, !adilla MA: Hypereosinophilic syndrome: Cutis: May 1BF212B+A,:@B002,
@B@: MMedlineN:
;;: &eller !4, 6u(ley 7%: 2he idiopathic hypereosinophilic syndrome: #loo!: May
1A 1BB@1F;+10,:27AB07B: MMedlineN:
Urticaria, )hoinergic
Article Last Updated: May 2A, 200E
AUTHOR AND EDITOR INFORMATION
)ection 1 of 11
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Author: 'erri Ho!(yn, MD, !rivate !ractice, 'iver *ity Dermatoloy
%erri Hos.yn is a mem(er of the follo$in medical societies: American Academy of
Dermatoloy
/ditors: Mar( 9 0e"$oh, MD, *hairman, Department of Dermatoloy, Mount )inai )chool of
Medicine1 Richard & 2in!on, MD, Assistant *linical !rofessor, Department of Dermatoloy,
2e3as 2ech University )chool of Medicine1 *onsultin )taff, Mountain 5ie$ Dermatoloy, !A1
)hri!ten M Mo$ad, MD, Assistant !rofessor, Department of Dermatoloy, 7eisiner Medical
*enter1 )atherine *uir(, MD, *linical Assistant !rofessor, Department of Dermatoloy, 6ro$n
University1 Dir( M E!ton, MD, Director, Department of Dermatoloy, 7eisiner Medical
*enter
Author and Editor Di!co!ure
#ynonym! and reated (ey$ord!+ cholineric urticaria, heat0induced urticaria, micropapular
urticaria, stress0induced urticaria
INTRODU)TION
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,ac(ground
*holineric urticaria is one of the physical urticarias (rouht on (y a physical stimulus: Althouh
the physical stimulus miht (e considered to (e heat, the actual precipitatin cause is s$eatin:
&atho-hy!ioogy
Mast cells seem to (e critically involved1 cholineric urticaria has (een used to study mast cell
activity: )erum histamine, the principal mediator, rises in concentration $ith e3perimentally
induced e3ercise, accompanied (y eosinophil and neutrophil chemotactic factors and tryptase: A
reduction of the alpha 10antichymotrypsin level, as seen in some other forms of urticaria, is
present, and the eruption is improved $ith dana9ol: 2hese findins have prompted some to arue
for proteases as a cause of histamine release:
Althouh mast cell release seems to (e involved, less eosinophilic ma<or (asic protein is present
than in many other forms of urticaria:
)everal factors, includin an increased incidence in patients $ith atopic dermatitis, a mar.ed
sensitivity in some patients $ith anaphylactic and anaphylactoid reactions, and an immediate
reactivity in some patients, suest an alleric (asis: =ne report sho$ed positive immediate
sensitivity to s$eat $ith passive transfer: )ome investiators, (ut not others, have reported
positive passive transfer: Another roup has recently reported a follicular pattern of cholineric
urticaria in s$eat0sensiti9ed patients (ut not in patients $ithout prominent sensitivity:
Autonomic functions are normal: =ne patient developed an accentuated response in a positive
copper test site, perhaps from either vasodilatation or aumentation of neuroloic stimulation: "n
one study, muscarinic receptors $ere reduced, (ut (indin $as normal: 2hermoraphy ostensi(ly
sho$s the areas of involvement:
/levation of histamine levels can (e detected at A minutes after e3ercise, reachin a pea. of 2A
n?mL at ;0 minutes: 2readmill e3ercise produces a sensation of enerali9ed s.in $armth,
follo$ed (y pruritus1 erythema1 urticaria1 and transient respiratory tract symptoms consistin of
shortness of (reath, $hee9in, or (oth: )tatistically sinificant decreases $ere o(served in 1
second forced e3piratory volumes, ma3imal mide3piratory flo$ rates, and specific conductance:
An increase in residual volume $as also detected:
Frequency
United #tate!
2he prevalence of cholineric urticaria is varia(le: Moore0'o(inson and &arin found that a(out
0:2H of patients in an outpatient dermatoloic clinic had cholineric urticaria: Ho$ever, many
pu(lished series have found cholineric urticaria to (e common: 2he prevalence is definitely
hiher in persons $ith urticaria1 cholineric urticaria affected 11H of a population $ith chronic
urticaria in one study, and A:1H of persons $ith urticaria in another study: 2he prevalence is
hiher in persons $ith atopic conditions +e, asthma, rhinitis, atopic ec9ema,, (ut this is (y no
means e3clusive: A rare familial form of the disease is also reported:
#e/
*holineric urticaria occurs in (oth men and $omen, (ut it seems to (e more common in men
than in $omen:
Age
2he condition usually (eins in people aed 100;0 years, $ith an averae ae at onset of
1E years in one study and a mean ae of 22 years in another study: "t persists for a
num(er of years: Most patients retain the tendency for many years:
"n one series of 22 persons, the averae duration $as 7:A years, $ith a rane of ;01E
years, (ut, in 7 patients on follo$0up study, some patients retained the tendency for ;0
years:
"n another study, almost BEH of patients $ere men, $ith a mean ae of 22 years, $hereas
in another roup, ;1 $omen and 2A men had cholineric urticaria:
)0INI)A0
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Hi!tory
Lesions appear rather rapidly, usually $ithin a fe$ minutes after the onset of s$eatin,
and they last from a half0hour to an hour or more, $ith a mean duration of a(out F0
minutes:
)ymptoms are sufficiently uncomforta(le to cause many patients to chane their patterns
of activity to prevent attac.s:

o )ymptoms seem to follo$ any stimulus to s$eat: A crucial point in cholineric

urticaria is not the actual temperature of the s.in surface, the averae s.in
temperature, or even the core temperature, (ut it is an increase or a decrease in the
$eihted averae (ody temperature:
o "n cholineric urticaria, $hether s.in lesions are provo.ed (y passive heatin of
the (ody at rest +e, saunali.e conditions, or (y active heatin at a lo$ am(ient
temperature is (asically related to the thermoreulatory process:
/3ercise is the most common precipitatin event, (ut any activity that causes s$eatin,
includin elevated environmental temperature, hot food, sauna (aths, immersion in hot
$ater, ustatory stimuli, emotional stress, and hemodialysis, can (rin on an attac. in
some persons:
)ome persons $ho report symptoms only durin the $inter months apparently have a
reaction only $hen e3posed to heat or heat0producin e3ercise $hile unacclimati9ed to
heat:
&hy!ica
=ften, itchin, (urnin, tinlin, $armth, or irritation precedes the onset of numerous
small +10@ mm in diameter, pruritic $heals $ith lare surroundin flares +see Media 4ile
1,:
Lesions may appear any$here on the (ody, e3cept on the palms or the soles and rarely in
the a3illae: )ometimes, flares are the only presentation:
!atients $ho are more severely affected may e3perience systemic symptomatoloy, such
as faintin, a(dominal crampin, diarrhea, salivation, and headaches:

o Hepatocellular in<ury, anioedema, asthma, anaphylactoid, and even anaphylactic

reactions are also reported:
o !ersons $ith cardiorespiratory symptoms include patients $ith increased
pulmonary resistance $ith acetylcholine challene, $hich may (e a limitin
factor in certain occupations +e, those relatin to aerospace,:
=ne form of cholineric urticaria, sometimes called cholineric erythema, is (elieved to
sho$ persistent and individual macules of short duration (ut $ith ne$ macules
continually appearin at ad<acent sites:
*holineric dermoraphism comprises a locali9ed distri(ution of typical tiny $heals that
appear after stro.in the s.in of some patients $ith cholineric urticaria:
A locali9ed form and a presentation $ith cold0induced urticarial lesions may occur:

o !atients $ith this condition e3perienced a enerali9ed reaction to cold am(ient air
and cold $ater +(ut a neative response to the ice0cu(e test,:
o *old urticaria and cold0induced cholineric urticaria may (e seen in a(out 1H of
patients $ith cold urticaria:
*holineric urticaria may also occur in the settin of ac8uired forms of enerali9ed
a(sence or decrease in s$eatin:

o )ome patients $ith ac8uired idiopathic enerali9ed hypohidrosis are theori9ed to

have a defect in the nerve0s$eat land <unction:
o )uperficial o(struction of the acrosyrinium has sometimes (een associated $ith
ac8uired enerali9ed hypohidrosis:
)au!e!
/3ercise and hot (aths e3acer(ate pruritus and provo.e lesions in previously unaffected
areas:
=ther dianostic considerations

o )ome reports of chronic urticaria include patients $ith cholineric urticaria, (ut
the morpholoy is different: Ho$ever, other physical urticarias $ith similar
lesions, such as a8uaenic urticaria, e3ist:
o
A8uaenic urticaria appears in response to $ater at (oth cold temperatures
and hot temperatures1 $hen e3posed to tap $ater at room temperature, the
lesions resem(le those of cholineric urticaria:
"n adreneric urticaria, $heals are surrounded (y vasoconstriction, and the
response to epinephrine and norepinephrine is positive:
o *ommonly, patients $ith one physical urticaria tend to have another physical
urticaria as $ell, sometimes precipitated (y the same stimulus:
o *holineric urticaria may (e accompanied (y cold urticaria, pressure urticaria,
and even a8uaenic urticaria:
DIFFERENTIA0#
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Urticaria, Acute
Urticaria, *hronic
Urticaria, *ontact )yndrome
Urticaria, Dermoraphism
Urticaria, !ressure
Urticaria, )olar
Urticarial 5asculitis
Other &ro"em! to "e )on!idered
Adreneric urticaria
A8uaenic urticaria
WORKU&
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0a" #tudie!
2he most relia(le $ay to reproduce the disease is to cause the patient to s$eat from a
stimulus, such as durin e3ercise +e, $al.in or runnin on a treadmill,:

o 2raditionally, an intradermal in<ection of either 0:0A mL of 0:002H

car(amylcholine chloride +car(achol, or 0:0A mL of 0:02H +0:01 m,
methacholine has (een used to produce a flare0up containin characteristic $heals
+often $ith satellites,: 2his outcome occurs in a(out A1H of patients: 2he same
flare0up may occur in persons $ithout this condition, (ut it is usually smaller and
$ithout $healin:
o #icotinic acid has also (een used at a dilution of 1:A00,000 or 1:100,000:
o Lesions of cholineric urticaria have even (een reproduced (y curare derivatives
+e, D0tu(ocurarine,:
o *holineric dermoraphism can (e reproduced (y stro.in the s.in, (y usin
methyl acetylcholine, or (y employin other stimuli that cause s$eatin:
TREATMENT
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Medica )are
)ometimes, an attac. can (e a(orted (y rapid coolin:
Antihistamines, includin cetiri9ine, are helpful: 2he response to cetiri9ine is important
(ecause some of the antihistaminic effect has (een attri(uted to antimuscarinic activity:
U5 liht has (een (eneficial in some patients, (ut one must (e circumspect a(out
contraindications to U5 liht:
Aspirin aravated the condition in A2H of patients $ith cholineric urticaria, $hich is
similar to other forms of urticaria:
4or patients $ith (oth cold urticaria and cholineric urticaria, .etotifen +$here availa(le,
may (e helpful: A(out E2H of patients e3perience a reduction in $heals, and EFH of
patients report reduced itchin: *ardiorespiratory symptoms also reportedly respond to
.etotifen:
Dana9ol can (e (eneficial ostensi(ly (ecause it elevates antichymotrypsin levels:
6eta0(loc.ers, such as propranolol, have (een reported to (e useful:
"n evaluatin any response to therapy, one must al$ays consider that the condition can
clear spontaneously:
6oth topically applied (en9oyl scopolamine and oral scopolamine (utyl(romide, $here
availa(le, may (e helpful in (loc.in the appearance of lesions after challene:
Diet
Modifyin oneKs diet may (e helpful (ecause attac.s can sometimes result from hot foods
and (everaes, hihly spiced foods, and alcohol:
MEDI)ATION
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2he oals of pharmacotherapy are to reduce mor(idity and to prevent complications:
Drug )ategory+ Antihistamines
2hese aents may control itchin (y (loc.in effects of endoenously released histamine:
Drug Name *etiri9ine +Oyrtec,
De!cri-tion
4orms a comple3 $ith histamine for H1 receptor
sites in (lood vessels, 7" tract, and respiratory
tract:
Adut Do!e A010 m != 8d
&ediatric Do!e
I2 years: #ot esta(lished
20A years: 2:A m != 8d
JA years: Administer as in adults
)ontraindication! Documented hypersensitivity
Interaction! "ncreases *#) to3icity of depressants
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution!
*aution in hepatic or renal dysfunction1 doses
hiher than 10 m?d may cause dro$siness
Drug Name Loratadine +*laritin,
De!cri-tion
)electively inhi(its peripheral histamine H1
receptors:
Adut Do!e 10 m?d != on empty stomach
&ediatric Do!e
I2 years: #ot esta(lished
20E years: A m?d != on empty stomach
JE years: Administer as in adults
)ontraindication! Documented hypersensitivity
Interaction!
Getocona9ole, erythromycin, procar(a9ine, and
alcohol may increase levels
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution! "nitiate therapy at lo$er dose in liver impairment
Drug Name Desloratadine +*larine3,
De!cri-tion
Lon0actin tricyclic histamine antaonist
selective for H1 receptor: A ma<or meta(olite of
loratadine, $hich after inestion is e3tensively
meta(oli9ed to active meta(olite ;0
hydro3ydesloratadine:
Adut Do!e A m != 8d
&ediatric Do!e
I12 years: #ot esta(lished
J12 years: Administer as in adults
)ontraindication!
Documented hypersensitivity to desloratadine or
loratadine
Interaction! Limited data e3ist1 erythromycin and .etocona9ole
increase desloratadine and ;0hydro3ydesloratadine
plasma concentrations, (ut no increase $as
o(served in clinically relevant adverse effects,
includin R2c
&regnancy
* 0 )afety for use durin prenancy has not (een
esta(lished:
&recaution!
Decrease dose in hepatic impairment1 rarely causes
pharynitis or dry mouth
FO00OW1U&
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Deterrence.&re7ention
!atients should avoid the precipitatin factors: 2hese factors include e3ercise and any activity
that causes s$eatin, such as elevated environmental temperature, hot food, sauna (aths,
immersion in hot $ater, ustatory stimuli, emotional stress, and hemodialysis, (ecause these can
(rin on an attac. in some persons:
&atient Education
4or e3cellent patient education resources, visit eMedicineKs Allery *enter and ).in, Hair, and
#ails *enter: Also, see eMedicineKs patient education article Hives and Anioedema:
A)KNOW0ED9MENT#
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2he authors and editors of eMedicine ratefully ac.no$lede the contri(utions of previous
author, %ere D 7uin, MD, 4A*!
X
, 4ormer !rofessor /meritus, Department of Dermatoloy,
University of Ar.ansas for Medical )ciences, to the development and $ritin of this article:
MU0TIMEDIA
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Media file 1: )o!e1u- 7ie$ !ho$! !ma urticaria $hea! $ithin arge erythematou!
3are!4
5ie$ 4ull )i9e "mae
Media type: !hoto
REFEREN)E#
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Ammann !, )ur(er /, 6ertel =: 6eta (loc.er therapy in cholineric urticaria: Am J
e!: Au 1BBB1107+2,:1B1: MMedlineN:
*onfino0*ohen ', 7old(er A, Maen /, et al: Hemodialysis0induced rash: a uni8ue case
of cholineric urticaria: J Allergy Clin Immunol: Dec 1BBA1BE+E !t 1,:10020@: MMedlineN:
*9u(als.i G, 'ud9.i /: #europsychic factors in physical
urticaria: 'ermatologica: 1B7711A@+1,:10@: MMedlineN:
4u.unaa A, 6ito 2, 2suru G, et al: 'esponsiveness to autoloous s$eat and serum in
cholineric urticaria classifies its clinical su(types: J Allergy Clin
Immunol: Au 200A111E+2,:;B70@02: MMedlineN:
Hirschmann %5, La$lor 4, /nlish %), et al: *holineric urticaria: A clinical and
histoloic study: Arch 'ermatol: Apr 1BF7112;+@,:@E207: MMedlineN:
"ta.ura /, Ura(e G, -asumoto ), et al: *holineric urticaria associated $ith ac8uired
enerali9ed hypohidrosis: report of a case and revie$ of the literature: #r J
'ermatol: #ov 200011@;+A,:10E@0E: MMedlineN:
%ori99o %L: *holineric urticaria: Arch 'ermatol: Apr 1BF7112;+@,:@AA07: MMedlineN:
Gierland '': !hysical alleries: AA Arch 'erm Syphilol: %ul 1BA;1EF+1,:E10
F: MMedlineN:
Go(ayashi H, Ai(a ), -amaishi 2, et al: *holineric urticaria, a ne$ pathoenic
concept: hypohidrosis due to interference $ith the delivery of s$eat to the s.in
surface: 'ermatology: 2002120@+;,:17;0F: MMedlineN:
Moore0'o(inson M, &arin '!: )ome clinical aspects of cholineric urticaria: #r J
'ermatol: Dec 1BEF1F0+12,:7B@0B: MMedlineN:
#a.a9ato -, 2amura #, =h.uma A, et al: "diopathic pure sudomotor failure: anhidrosis
due to deficits in cholineric transmission: Neurology: =ct 2E 200@1E;+F,:1@7E0
F0: MMedlineN:
)oter #A, &asserman )": !hysical urticaria?anioedema: an e3perimental model of mast
cellactivation in humans: J Allergy Clin Immunol: #ov 1BF01EE+A,:;AF0EA: MMedlineN:
2sunemi -, "hn H, )ae.i H, 2ama.i G: *holineric urticaria successfully treated $ith
scopolamine (utyl(romide: Int J 'ermatol: =ct 200;1@2+10,:FA0: MMedlineN:
2up.er 'A, Doelas HM: &ater vapour loss threshold and induction of cholineric
urticaria: 'ermatologica: 1BB011F1+1,:2;0A: MMedlineN:
&arin ', *hampion ': Urticaria: !hiladelphia: &6 )aunders11B7@:1;E01@@:
Urticaria, Acute
Article Last Updated: Mar 1E, 2007
AUTHOR AND EDITOR INFORMATION
)ection 1 of 11
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Author: Henry K Wong, MD, &hD, )enior !rofessional )taff, Department of Dermatoloy,
Henry 4ord Hospital
Henry G &on is a mem(er of the follo$in medical societies: American Academy of
Dermatoloy, American Association of "mmunoloists, and )ociety for "nvestiative
Dermatoloy
/ditors: Danie ' Hogan, MD, Affiliate 2eachin 4aculty, )un *oast Hospital1 "nvestiator, Hill
2op 'esearch, 4lorida 'esearch *enter1 Richard & 2in!on, MD, Assistant *linical !rofessor,
Department of Dermatoloy, 2e3as 2ech University )chool of Medicine1 *onsultin )taff,
Mountain 5ie$ Dermatoloy, !A1 'e33rey & )aen, MD, !rofessor of Medicine, *hief, Division
of Dermatoloy, University of Louisville )chool of Medicine1 'oe M 9e3and, MD, M#)E,
Medical Director, *linical )tudies Unit, Assistant !rofessor, Department of Dermatoloy,
Associate )cholar, *enter for *linical /pidemioloy and 6iostatistics, University of
!ennsylvania1 Wiiam D 'ame!, MD, !aul ' 7ross !rofessor of Dermatoloy, University of
!ennsylvania )chool of Medicine1 5ice0*hair, !roram Director, Department of Dermatoloy,
University of !ennsylvania Health )ystem
Author and Editor Di!co!ure
#ynonym! and reated (ey$ord!+ hives, allery, alleric reaction, anaphyla3is, anaphylactoid
reaction, anioedema, immune0mediated urticaria, nonimmune0mediated urticaria, non0immune0
mediated urticaria, urticaria, rash, dru rash, viral rash
INTRODU)TION
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,ac(ground
Urticaria $as first descri(ed in the /nlish literature in 1772, althouh the disease has (een
reconi9ed throuhout history: 2he disorder is mar.ed (y the onset of evanescent $heals +hives,
associated $ith pruritus: Acute urticaria is a common disorder that often prompts patients to see.
treatment in the emerency department +/D,: "n fact, it is the most common cutaneous disease
treated in the /D: 2he eruption is symptomatic and can (e visually apparent over many different
parts of the s.in: 2he natural course of the acute disease lasts from a one0time event of several
hoursK duration up to E $ee.s, dependin on the etioloy: "f urticaria is present continuously over
a E0$ee. period, it is cateori9ed as chronic urticaria: "nformation on this entity is availa(le in
Urticaria, *hronic: Additionally, the Medscape Allery 'esource *enter may (e helpful:
"ndividual lesions appear at different locations and fade $ithout scarrin, often in a matter of
hours: "n A0H of patients, a specific etioloy can (e identified: 6rief episodes of urticaria can (e
associated $ith identifia(le causes, and the method of e3posure +ie, direct contact, oral or
intravenous routes, is usually .no$n: "f the location of the $heals remains fi3ed for loner than
2@ hours, the dianosis may (e urticarial vasculitis or (ullous pemphioid:
&atho-hy!ioogy
2he release of histamine and other compounds (y mast cells and (asophils causes the appearance
of urticaria: "mmune "mmune0mediated urticaria is from immunolo(ulin / +"/, (indin
specific antien and the comple3 (indin to 4c/'1 receptors to activate mast cells: Mast cell
activation from crosslin.in of 4c/'1 receptor causes deranulation of intracellular vesicles that
contain histamine, leu.otriene *@, prostalandin D2, and other chemotactic mediators that
recruit eosinophils and neutrophils into the dermis: Histamine and chemo.ine release lead to
e3travasation of fluid into the dermis +edema,: Histamine effects account for many of the clinical
and histoloic findins of urticaria:
Histamine is the liand for at least 2 types of mem(rane0(ound receptors, H1 and H2 receptors,
$hich are present on numerous cells: 2he activation of H1 histamine receptors on smooth muscle
cells and endothelial cells leads to cellular contraction and increased vascular permea(ility: 2he
activation of H2 histamine receptors causes vasodilation: Urticaria is a reaction pattern that
reflects the activation of mast cells and (asophils: 2he e3act mechanism of action resultin in the
release of the intracellular contents of mast cells and (asophils is varied and can occur throuh
immune0mediated or nonDimmune0mediated mechanisms:
Immune1mediated urticaria
"mmune0mediated urticaria can (e caused (y ; of @ types of immune mechanisms:
2he type " alleric "/ response is initiated (y antien0mediated "/ immune comple3es
that (ind and cross0lin. 4c receptors on the surface of mast cells and (asophils: 2he types
of antiens that (ind to "/ are varied and include proteins, polysaccharides, and other
immunoenic molecules:
2ype "" responses are mediated (y cytoto3ic 2 cells: 2he disease process activates
(yproducts that cause urticarial vasculitis or (ullous pemphioid:
2ype """ immune0comple3 disease is associated $ith systemic lupus erythematosus and
other connective tissue disorders that activate urticaria:
Non:immune1mediated
*hemicals that can directly induce mast cell deranulation, presuma(ly (y alterin the
mem(rane properties, cause nonDimmune0mediated urticaria: *ommon aents associated $ith
direct mast cell activation are opiates, anti(iotics, curare, radiocontrast media, a9o dyes, aspirin,
and aspirin derivatives:
Frequency
United #tate!
Urticaria affects 1A020H of the population at some point in their lives:
Internationa
2he international fre8uency is similar to the U) fre8uency:
Mortaity.Mor"idity
Acute urticaria causes discomfort, (ut it does not cause mortality unless it is associated $ith
anioedema involvin the upper air$ays:
1, 2, ;
Race
#o variation in race is reported:
#e/
4emales have a slihtly hiher prevalence +E1H, than males:
Age
Acute urticaria affects persons of all ae roups: 2he mean ae of persons $ho are affected is in
the second to third decade of life:
)0INI)A0
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Hi!tory
Acute urticaria is characteri9ed (y the onset of clinically apparent, edematous, evanescent,
erythematous pla8ues: "ndividual lesions remain for less than 2@ hours, e3hi(itin a transitory
and miratory (ehavior: 2he etioloy can (e inferred in as many as A0H of ne$ cases: "n
eneral, reater than F0H of ne$0onset urticaria resolves in 2 $ee.s and reater than BAH of
ne$0onset cases resolve (y ; months: Atopy can often (e identified in the patient or his or her
family mem(ers: &hen urticaria persists for more than E $ee.s, it is considered chronic
urticaria: Additional etioloies e3ist for chronic urticaria: A thorouh medical evaluation is
indicated to eliminate the possi(ility of treata(le causes of urticaria, $hich include malinancies,
connective tissue disorders, and chronic infections:
Acute urticaria is commonly caused (y a variety of infections, medications, food
alleries, physical stimulants, chemicals, chronic inflammatory diseases, and insect (ites,
as follo$s:

o 'ecent infection from a viral syndrome or an upper respiratory illness +;BH,

o Medications +e, A*/ inhi(itors, aspirin, nonsteroidal anti0inflammatory drus,
sulfa0(ased drus, penicillins, diuretics, opioids, polymy3in 6,
o 4ood and food additives +e, nuts, fish, shellfish, es, chocolate, stra$(erries,
salicylate, (en9oates,
o !arasitic infections +e, Ascaris/ Ancylostoma/ Strongyloi!es/ Echinococcus/
+richinella/ )ilaria,
o !hysical stimulants +e, cold, pressure, a8uaenic,
o *hemicals +e, late3, ammonium persulfate in hair chemicals,
o "ntravenous radiocontrast media
o Arthropod (ites
#e$0onset fever and constitutional symptoms suest chronic autoimmune disease:
&hy!ica
Lesions of urticaria can (e polymorphic and vary from several millimeters to lare, continuous
pla8ues:
!la8ues have smooth surfaces $ith polycyclic curved (orders: Lesions do not have
scales:
Lesions sho$ an intense erythema in the ne$est areas, $ith a trailin clearin reion in
older areas:
*entral clearin can cause a taret confiuration in e3pandin pla8ues: 2he advancin
(order sho$s a discrete ede follo$ed (y a faint, trailin, diffuse (order:
Lesions last less than 2@ hours, and scars do not develop:
/rythema multiforme can resem(le urticaria:

o 6oth processes can (e a reaction to medication:

o /arly lesions of erythema multiforme may appear edematous, round, taretoid,
and polycyclic as the lesion e3pands: Ho$ever, in erythema multiforme, each
lesion can (e differentiated (y the stationary nature and the proression to a dus.y
color $ith (ulla formation:
)au!e!
A definitive incitin aent can (e identified in @00A0H of cases of acute urticaria:
"n one recent study, causes $ere identified as an upper respiratory tract infection in
;B:AH of the total cases, analesics in BH, and food intolerance in 0:BH:
Urticaria associated $ith the onset of autoimmune disorders or malinancy +e, systemic
lupus erythematosus, lymphoma, $ill (ecome chronic:
Most cases of ne$0onset urticaria are idiopathic in nature:
DIFFERENTIA0#
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6ullous !emphioid
/rythema Multiforme
Mastocytosis
!ruritic Urticarial !apules and !la8ues of !renancy
Urticaria, *hronic
Urticaria, *ontact )yndrome
Urticarial 5asculitis
WORKU&
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0a" #tudie!
#o specific la(oratory study is needed unless the patientKs history suests a particular
dianostic test: *arefully o(tain a complete medical and travel history to e3clude a ne$
presentation of infectious or medical pro(lems: A thorouh revie$ of systems is essential:
Imaging #tudie!
=(tain imain studies if indicated (y the patientKs history:
Other Te!t!
=(tain other tests if indicated (y the patientKs history:
&rocedure!
#o procedures are necessary for the dianosis of acute urticaria: "f the lesion remains for
loner than 2@ hours or if it (listers, a s.in (iopsy is suested to investiate for other
possi(ilities in the differential dianosis:
Hi!toogic Finding!
2he histoloic findins of acute urticaria are not dramatic: #o epidermal chane is present: 2he
dermis may sho$ increased spacin (et$een collaen fi(ers, suestive of dermal edema:
Dilated lymphatics and dilated capillaries can (e seen in the involved s.in: A sparse,
perivascular, lymphocytic infiltrate and a fe$ eosinophils may (e present: Mast cells are
increased in num(er in the involved s.in:
@
TREATMENT
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Medica )are
2o prevent recurrence, identify the incitin aent and instruct the patient to avoid it:
2he cause is not .no$n in reater than A0H of the cases: 2he most commonly identified
cause is a recent infection or viral syndrome, and, under these circumstances, the patient
should (e informed of the self0limitin duration of the disorder:
!alliation of pruritus and discomfort associated $ith the lesions is the primary oal of
treatment in the initial visit: 2herapy aims to (loc. histamine action: *lasses of drus to
consider are H1 antihistamines, H2 antihistamines, lucocorticoids, and tricyclic
antidepressants that have com(ined H1 and H2 antaonists +e, do3epin,:
#urgica )are
#one
)on!utation!
*onsult appropriate specialists as indicated (y the patientKs history and a thorouh revie$ of
systems:
Diet
/ducate patients to avoid food and food additives if identified as the cause of urticaria:
'evie$ medications to screen for the use of aspirin, salicylates, and nonsteroidal anti0
inflammatory drus: "f identified, these nonimmunoloic histamine releasers should (e
discontinued:
MEDI)ATION
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2he dru of choice for control of urticaria is an H1 antihistamine: #umerous choices are
availa(le from this roup, each $ith a different adverse effect profile: 2he choice is (ased on the
patientKs needs and tolera(ility to a particular antihistamine: &ith the num(er of nonsedatin
antihistamines availa(le today, these aents should (e tried first to facilitate disappearance of the
lesions and symptoms of pruritus: 2o achieve optimal control of urticaria, try different aents or
increase the dose to ma3imum tolera(le levels for that aent: "n difficult cases, a com(ination of
H1 and H2 antihistamines may (e more effective: Do3epin has (oth H1 antihistaminic properties
and H2 antihistaminic properties and can (e used $hen a sinle H1 aent fails to control disease
activity: )evere or refractory urticaria may (enefit from a taperin course of prednisone in
com(ination $ith an antihistamine aent:
Drug )ategory+ Antihistamines
#e$er nonsedatin antihistamines may (e tried initially to control urticaria: Aents include
fe3ofenadine, loratadine, desloratadine, and cetiri9ine: "f additional antihistamines are needed,
traditional aents can (e considered: 2he E traditional classes of antihistamines are al.ylamine,
ethylenediamine, ethanolamine, propylamine, phenothia9ine, and pipera9ine: /ach has different
adverse effects that may vary amon individuals: #onsedatin H1 antihistamines $ith similar
effectiveness in the treatment of urticaria are availa(le: 2he choices for treatment are (road, and
therapeutic options are tailored to the patient: 2he e3amples of drus (elo$ do not represent the
preferred aents or the specific recommendation of the author: =ther antihistamines should also
(e considered and revie$ed (efore treatment:
Drug Name
Diphenhydramine +6enadryl, 6enylin, Diphen,
AllerMa3,
De!cri-tion 4or symptomatic relief of symptoms caused (y
release of histamine in alleric reactions:
/thanolamine antihistamine that is commonly
prescri(ed: *an (e purchased over0the0counter, (ut
prescription doses are often necessary: )edation is
an associated effect:
Adut Do!e 2A0A0 m != 8E0Fh prn1 not to e3ceed @00 m?d
&ediatric Do!e
A m?. != 8d in divided doses1 not to e3ceed ;00
m?d
)ontraindication! Documented hypersensitivity1 MA="s
Interaction!
!otentiates effect of *#) depressants1 (ecause of
alcohol content, do not ive syr dosae form to
patient ta.in medications that can cause
disulfiramli.e reactions
&regnancy
* 0 4etal ris. revealed in studies in animals (ut not
esta(lished or not studied in humans1 may use if
(enefits out$eih ris. to fetus
&recaution!
*an e3acer(ate conditions associated $ith
increased cholineric tone +e, anle0closure
laucoma1 urinary retention1 dryness of the mouth,
nose, and throat,1 other effects include vertio,
visual distur(ance, tremors, and impotence1 may
e3acer(ate hyperthyroidism and peptic ulcer1 has
(een associated $ith R2 prolonation at to3ic
doses
Drug Name Hydro3y9ine +Atara3, 5istaril,
De!cri-tion
Antaoni9es H1 receptors in periphery: May
suppress histamine activity in su(cortical reion of
*#): !ipera9ine type of antihistamine that is
effective and has fe$er sedatin effects compared
$ith diphenhydramine: Usually $ell tolerated in
most individuals:
Adut Do!e 2A0100 m != 8d?8id
&ediatric Do!e 2 m?.?d !=1 0:E m?.?dose != 8Eh
)ontraindication! Documented hypersensitivity
Interaction!
*#) depression may increase $ith alcohol or other
*#) depressants
&regnancy
* 0 4etal ris. revealed in studies in animals (ut not
esta(lished or not studied in humans1 may use if
(enefits out$eih ris. to fetus
&recaution! Associated $ith clinical e3acer(ations of porphyria
+may not (e safe for patients $ith porphyria,1 /*7
a(normalities +alterations in 2 $aves, may occur1
may cause dro$siness
Drug Name Loratadine +*laritin,
De!cri-tion
#onsedatin antihistamine that has lon0actin
characteristics: )electively inhi(its peripheral
histamine H1 receptors:
Adut Do!e 10 m?d != on empty stomach
&ediatric Do!e
I2 years: #ot esta(lished
20E years: A m?d != on empty stomach
JE years: Administer as in adults
)ontraindication! Documented hypersensitivity
Interaction!
Getocona9ole, erythromycin, procar(a9ine, and
alcohol may increase loratadine levels
&regnancy
6 0 4etal ris. not confirmed in studies in humans
(ut has (een sho$n in some studies in animals
&recaution!
"nitiate therapy at lo$er dose or administer 8od in
liver impairment
Drug Name *etiri9ine +Oyrtec,
De!cri-tion
)econd0eneration antihistamine $ith mar.edly
reduced sedative effects and reduced
anticholineric effects: 4orms comple3 $ith
histamine for H1 receptor sites in (lood vessels, 7"
tract, and respiratory tract:
Adut Do!e A010 m != 8d
&ediatric Do!e
I2 years: #ot esta(lished
20A years: 2:A m != 8d
JA years: Administer as in adults
)ontraindication! Documented hypersensitivity
Interaction! "ncreases *#) to3icity of depressants
&regnancy
6 0 4etal ris. not confirmed in studies in humans
(ut has (een sho$n in some studies in animals
&recaution!
*aution in hepatic or renal dysfunction1 doses J10
m?d may cause dro$siness
Drug Name Desloratadine +*larine3,
De!cri-tion Lon0actin tricyclic histamine antaonist
selective for H1 receptor: 'elieves nasal
conestion and systemic effects of seasonal allery:
"s a ma<or meta(olite of loratadine, $hich, after
inestion, is meta(oli9ed e3tensively to active
meta(olite ;0hydro3ydesloratadine:
Adut Do!e A m != 8d
&ediatric Do!e
I12 years: #ot esta(lished
J12 years: Administer as in adults
)ontraindication! Documented hypersensitivity
Interaction!
Limited data e3ist1 erythromycin and .etocona9ole
increase desloratadine and ;0hydro3ydesloratadine
plasma concentrations, (ut no increase in clinically
relevant adverse effects, includin R2c, is
o(served
&regnancy
* 0 4etal ris. revealed in studies in animals (ut not
esta(lished or not studied in humans1 may use if
(enefits out$eih ris. to fetus
&recaution!
Decrease dose in hepatic impairment1 rarely causes
pharynitis or dry mouth
Drug Name 4e3ofenadine +Allera,
De!cri-tion
*ompetes $ith histamine for H1 receptors on 7"
tract, (lood vessels, and respiratory tract, reducin
hypersensitivity reactions: Does not sedate:
Adut Do!e
"': E0 m != (id
)': 1F0 m != 8d
&ediatric Do!e
IE years: #ot recommended
E012 years: ;0 m != (id
J12 years: Administer as in adults
)ontraindication! Documented hypersensitivity
Interaction!
2o3icity increases $ith coadministration of
erythromycin and .etocona9ole
&regnancy
* 0 4etal ris. revealed in studies in animals (ut not
esta(lished or not studied in humans1 may use if
(enefits out$eih ris. to fetus
&recaution! #o data availa(le on use $hile (reastfeedin
Drug )ategory+ Corticosteroids
!rednisone taper can (e effective $hen com(ined $ith an antihistamine:
Drug Name !rednisone +Deltasone, =rasone, )terapred,
De!cri-tion Useful in cases that have not responded to
traditional antihistamine: 4or e3tensive
symptomatic urticaria, a (urst of prednisone over @
d can lead to mar.ed improvement and control of
symptoms:
Adut Do!e
@0 m != 8d (urst over @ d in com(ination $ith
antihistamine1 $hen used alone, taper over 2 $.
&ediatric Do!e 102 m?.?d != taper over 2 $.
)ontraindication!
Documented hypersensitivity1 viral, funal,
connective tissue, or tu(ercular s.in infections1
peptic ulcer disease1 hepatic dysfunction1 7"
disease
Interaction!
*oadministration $ith estroens may decrease
clearance1 $hen used $ith dio3in, diitalis
to3icity may increase secondary to hypo.alemia1
pheno(ar(ital, phenytoin, and rifampin may
increase meta(olism +consider increasin
maintenance dose,1 monitor for hypo.alemia $ith
coadministration of diuretics
&regnancy
6 0 4etal ris. not confirmed in studies in humans
(ut has (een sho$n in some studies in animals
&recaution!
A(rupt discontinuation may cause adrenal crisis1
hyperlycemia, edema, osteonecrosis, myopathy,
peptic ulcer disease, hypo.alemia, osteoporosis,
euphoria, psychosis, myasthenia ravis, ro$th
suppression, and infections may occur
Drug )ategory+ Tricyclic antidepressants
Do3epin has (een used in urticaria and pruritus:
Drug Name Do3epin +)ine8uan, Oonalon,
De!cri-tion
"nhi(its histamine and acetylcholine activity: Has
(oth H1 antaonist activity and H2 antaonist
activity that is far more potent than traditional
antihistamines: Has antidepressant properties
attri(uted to (loc.in MA=:
Adut Do!e 1002A m != tid
&ediatric Do!e
I12 years: #ot recommended
J12 years: 2A0A0 m?d != hs or (id?tid and
increase radually to 100 m?d
)ontraindication!
Documented hypersensitivity1 urinary retention1
acute recovery phase follo$in M"1 laucoma
Interaction! Decreases antihypertensive effects of clonidine (ut
increases effects of sympathomimetics and
(en9odia9epines1 effects of desipramine increase
$ith phenytoin, car(ama9epine, and (ar(iturates
&regnancy
* 0 4etal ris. revealed in studies in animals (ut not
esta(lished or not studied in humans1 may use if
(enefits out$eih ris. to fetus
&recaution!
*aution in cardiovascular disease, conduction
distur(ances, sei9ure disorders, urinary retention,
and hyperthyroidism1 caution in patients receivin
thyroid replacement
Drug )ategory+ Histamine H2 antagonists
Used for treatment of duodenal ulcer disease1 ho$ever, can (e used in com(ination $ith H1
antihistamines $hen H1 antihistamines alone do not provide ade8uate relief:
Drug Name *imetidine +2aamet,
De!cri-tion
H2 antaonist that $hen com(ined $ith an H1
antaonist may (e useful in treatin itchin and
flushin in urticaria and contact dermatitis that do
not respond to H1 antaonists alone: Use in
addition to H1 antihistamines:
Adut Do!e ;00 m != 8id1 not to e3ceed 2@00 m?d
&ediatric Do!e
I12 years: #ot esta(lished
J12 years: 200@0 m?.?d !=
)ontraindication! Documented hypersensitivity
Interaction!
*an increase (lood levels of theophylline,
$arfarin, 2*As, triamterene, phenytoin, 8uinidine,
propranolol, metronida9ole, procainamide, and
lidocaine
&regnancy
6 0 4etal ris. not confirmed in studies in humans
(ut has (een sho$n in some studies in animals
&recaution!
Altered astric acidity can affect a(sorption of
cyclosporine and .etocona9ole1 elderly persons
may e3perience confusional states1 may cause
impotence and ynecomastia in youn males1 may
increase levels of many drus1 ad<ust dose or
discontinue treatment if chanes in renal function
occur
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Further In-atient )are
Acute urticaria restricted to the s.in does not re8uire hospitali9ation and can (e manaed
$ith outpatient care:
)hortness of (reath suests respiratory involvement and a dianosis of anioedema: "n
this situation, the patient should (e monitored in the /D until normal air$ay function is
restored:
Further Out-atient )are
!atients $ith acute urticaria can (e treated in an outpatient settin to assess the efficacy
of the treatment plan:
A dermatoloist should e3amine patients in @0E $ee.s to determine if urticaria may (e
chronic in nature:
Deterrence.&re7ention
!atients should avoid .no$n precipitatin aents:
&rogno!i!
Acute urticaria is self0limited and usually resolves in less than ; $ee.s:
&atient Education
'eassure the patient that the disorder is often limited in duration: "f an incitin aent can
(e identified, teach avoidance:
4or e3cellent patient education resources, visit eMedicineKs Allery *enter and ).in,
Hair, and #ails *enter: Also, see eMedicineKs patient education article Hives and
Anioedema:
MI#)E00ANEOU#
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Medica.0ega &it3a!
4ailure to educate the patient on the adverse effects and the dru interactions of the
medications is a pitfall: *arefully inform patients a(out the adverse effects of
antihistamines +e, sedation, and potential dru interactions:
MU0TIMEDIA
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Media file 1: Urticaria 3rom drug reaction4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 2: Acute urticaria in a todder a33ecting the 3ace4 0i(ey cau!e i! -o!t7ira
!yndrome4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file ;: Acute urticaria a!!ociated $ith dermatogra-hi!m4
5ie$ 4ull )i9e "mae
Media type: !hoto
REFEREN)E#
)ection 11 of 11
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1: 6eltrani 5): Urticaria and anioedema: 'ermatol Clin: %an 1BBE11@+1,:1710
1BF: MMedlineN:
2: )oter #A: Acute and chronic urticaria and anioedema: J Am Aca!
'ermatol: %ul 1BB112A+1 !t 2,:1@E0A@: MMedlineN:
;: 5aradara<ulu ): Urticaria and anioedema: *ontrollin acute episodes, copin $ith
chronic cases: Postgra! e!: May 200A1117+A,:2A0;1: MMedlineN:
@: Haas #, 2oppe /, Hen9 6M: Microscopic morpholoy of different types of
urticaria: Arch 'ermatol: %an 1BBF11;@+1,:@10E: MMedlineN:
A: 6ae %), Gim )H, -e -M, -oon H%, )uh *H, #ahm DH, et al: )inificant association of
4cepsilon'"alpha promoter polymorphisms $ith aspirin0intolerant chronic urticaria: J
Allergy Clin Immunol: 4e( 2007111B+2,:@@B0AE: MMedlineN:
E: Di((ern DA %r: Urticaria: selected hihlihts and recent advances: e! Clin North
Am: %an 200E1B0+1,:1F7020B: MMedlineN:
7: 7reaves M&, )a(roe 'A: A6* of alleries: Allery and the s.in: "00Urticaria: #J: Apr
11 1BBF1;1E+71;F,:11@70A0: MMedlineN:
F: Humphreys 4, Hunter %A: 2he characteristics of urticaria in ;B0 patients: #r J
'ermatol: Apr 1BBF11;F+@,:E;A0F: MMedlineN:
B: Monroe /&: Loratadine in the treatment of urticaria: Clin +her: Mar0
Apr 1BB711B+2,:2;20@2: MMedlineN:
10: Mortureu3 !, LPautP0La(rY9e *, Lerain0Lifermann 5, Lamireau 2, )arlanue %, 2aZe(
A: Acute urticaria in infancy and early childhood: a prospective study: Arch
'ermatol: Mar 1BBF11;@+;,:;1B02;: MMedlineN:
11: !ollac. *5 %r, 'omano 2%: =utpatient manaement of acute urticaria: the role of
prednisone: Ann Emerg e!: #ov 1BBA12E+A,:A@70A1: MMedlineN:
12: )ac.esen *, )e.erel 6/, =rhan 4, Goca(as *#, 2uncer A, Adaliolu 7: 2he etioloy of
different forms of urticaria in childhood: Pe!iatr 'ermatol: Mar0Apr 200@121+2,:1020
F: MMedlineN:
1;: )imonart 2, As.enasi ', Lheureu3 !: !articularities of urticaria seen in the emerency
department: Eur J Emerg e!: %un 1BB@11+2,:F002: MMedlineN:
1@: )later %&, Oechnich AD, Ha3(y D7: )econd0eneration antihistamines: a comparative
revie$: 'rugs: %an 1BBB1A7+1,:;10@7: MMedlineN:
1A: Ou(er(ier 2, "ffl[nder %, )emmler *, Hen9 6M: Acute urticaria: clinical aspects and
therapeutic responsiveness: Acta 'erm -enereol: %ul 1BBE17E+@,:2BA07: MMedlineN:
Urticaria, Acute excerpt
Article Last Updated: Mar 1, 2007
Drug Eru-tion!
Article Last Updated: Mar 2F, 2007
AUTHOR AND EDITOR INFORMATION
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Author: 'onathan E ,ume, MD, "nstructor in *linical Dermatoloy, *olum(ia University
*ollee of !hysicians and )ureons1 *onsultin )taff, &est$ood Dermatoloy and
Dermatoloic )urery 7roup, !A
%onathan / 6lume is a mem(er of the follo$in medical societies: Alpha =mea Alpha,
American Academy of Dermatoloy, American *ontact Dermatitis )ociety, American Medical
Association, American )ociety for Dermatoloic )urery, "nternational )ociety of Dermatoloy,
and #ational !soriasis 4oundation
*oauthor+s,: Thoma! N Hem, MD, *linical Associate !rofessor, Departments of Dermatoloy
and !atholoy, )tate University of #e$ -or. at 6uffalo1 Director, 6uffalo Medical 7roup
Dermatopatholoy La(oratory1 Michee Ehrich, MD, 4ello$ for the American Academy of
*osmetic )urery, )taff !hysician, Department of Dermatoloy, La %olla )paMD1 )hare!
)ami!a, MD, Head of *linical Dermatoloy, 5ice0*hair, Department of Dermatoloy,
*leveland *linic 4oundation
/ditors: Nei #hear, MD, !rofessor and *hief of Dermatoloy, !rofessor of Medicine, !ediatrics
and !harmacoloy, University of 2oronto 4aculty of Medicine1 Head of Dermatoloy,
)unny(roo. &omenKs *ollee Health )ciences *enter and &omenKs *ollee Hospital, *anada1
Richard & 2in!on, MD, Assistant *linical !rofessor, Department of Dermatoloy, 2e3as 2ech
University )chool of Medicine1 *onsultin )taff, Mountain 5ie$ Dermatoloy, !A1 'e33rey &
)aen, MD, !rofessor of Medicine, *hief, Division of Dermatoloy, University of Louisville
)chool of Medicine1 )atherine *uir(, MD, *linical Assistant !rofessor, Department of
Dermatoloy, 6ro$n University1 Dir( M E!ton, MD, Director, Department of Dermatoloy,
7eisiner Medical *enter
Author and Editor Di!co!ure
#ynonym! and reated (ey$ord!+ adverse cutaneous dru reactions, cutaneous reaction to
drus, dru0induced cutaneous reactions, mucocutaneous dru reactions, dermatoses, dermatosis,
cutaneous eruptions, cutaneous dru reactions, adverse dru reactions, dru allery, fi3ed dru
reactions, medication adverse effects, medication side effects, adverse effects, side effects,
medication allery
INTRODU)TION
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,ac(ground
Dru eruptions can mimic a $ide rane of dermatoses: 2he morpholoies are myriad and include
mor(illiform +most common, see Media file 1,, urticarial, papulos8uamous, pustular, and
(ullous: Medications can also cause pruritus and dysesthesia $ithout an o(vious eruption:
A dru0induced reaction should (e considered in any patient $ho is ta.in medications and $ho
suddenly develops a symmetric cutaneous eruption: Medications that are .no$n for causin
cutaneous reactions include antimicro(ial aents, nonsteroidal anti0inflammatory drus
+#)A"Ds,, cyto.ines, chemotherapeutic aents, anticonvulsants, and psychotropic aents:
!rompt identification and $ithdra$al of the offendin aent may help limit the to3ic effects
associated $ith the dru: 2he decision to discontinue a potentially vital dru often presents a
dilemma:
&atho-hy!ioogy
Dru eruptions may (e divided into immunoloically and nonimmunoloically mediated
reactions:
Immunoogicay mediated reaction!
*oom(s and 7ell proposed @ types of immunoloically mediated reactions, as follo$s:
2ype " is immunolo(ulin / +"/,Ddependent reactions, $hich result in urticaria,
anioedema, and anaphyla3is +see Media file 1A,:
2ype "" is cytoto3ic reactions, $hich result in hemolysis and purpura +see Media file B,:
2ype """ is immune comple3 reactions, $hich result in vasculitis, serum sic.ness, and
urticaria:
2ype "5 is delayed0type reactions $ith cell0mediated hypersensitivity, $hich result in
contact dermatitis, e3anthematous reactions, and photoalleric reactions:
"nsulin and other proteins are associated $ith type " reactions: !enicillin, cephalosporins,
sulfonamides, and rifampin are .no$n to cause type "" reactions: Ruinine, salicylates,
chlorproma9ine, and sulfonamides can cause type """ reactions: 2ype "5 reactions, the most
common mechanism of dru eruptions, are often encountered in cases of contact hypersensitivity
to topical medications, such as neomycin: )ulfonamides are most fre8uently associated $ith
to3ic epidermal necrolysis +2/#,:
Althouh most dru eruptions are type "5 hypersensitivity reactions, only a minority are "/0
dependent: 2hat is, anti(odies can (e demonstrated in less than AH of cutaneous dru reactions:
2ype "5 cell0mediated reactions are not dose dependent, they usually (ein 7020 days after the
medication is started, they may involve (lood or tissue eosinophilia, and they may recur if drus
chemically related to the causative aent are administered:
Nonimmunoogicay mediated reaction!
#onimmunoloically mediated reactions may (e classified accordin to the follo$in features:
accumulation, adverse effects, direct release of mast cell mediators, idiosyncratic reactions,
intolerance, %arisch0Her3heimer phenomenon, overdosae, or phototo3ic dermatitis: +)ymptoms
of %arisch0Her3heimer reactions disappear $ith continued therapy: Dru therapy should (e
continued until the infection is fully eradicated:,
An e3ample of accumulation is aryria +(lue0ray discoloration of s.in and nails, o(served $ith
use of silver nitrate nasal sprays:
Adverse effects are normal (ut un$anted effects of a dru: 4or e3ample, antimeta(olite
chemotherapeutic aents, such as cyclophosphamide, are associated $ith hair loss:
2he direct release of mast cell mediators is a dose0dependent phenomenon that does not involve
anti(odies: 4or e3ample, aspirin and other #)A"Ds cause a shift in leu.otriene production,
$hich triers the release of histamine and other mast0cell mediators: 'adioraphic contrast
material, alcohol, cyto.ines, opiates, cimetidine, 8uinine, hydrala9ine, atropine, vancomycin, and
tu(ocurarine also may cause release of mast0cell mediators:
"diosyncratic reactions are unpredicta(le and not e3plained (y the pharmacoloic properties of
the dru: An e3ample is the individual $ith infectious mononucleosis $ho develops a rash $hen
iven ampicillin:
"m(alance of endoenous flora may occur $hen antimicro(ial aents preferentially suppress the
ro$th of one species of micro(e, allo$in other species to ro$ viorously: 4or e3ample,
candidiasis fre8uently occurs $ith anti(iotic therapy:
"ntolerance may occur in patients $ith altered meta(olism: 4or e3ample, individuals $ho are
slo$ acetylators of the en9yme N0acetyltransferase are more li.ely than others to develop dru0
induced lupus in response to procainamide:
%arisch0Her3heimer phenomenon is a reaction due to (acterial endoto3ins and micro(ial antiens
that are li(erated (y the destruction of microoranisms: 2he reaction is characteri9ed (y fever,
tender lymphadenopathy, arthralias, transient macular or urticarial eruptions, and e3acer(ation
of pree3istin cutaneous lesions: 2he reaction is not an indication to stop treatment (ecause
symptoms resolve $ith continued therapy: 2his reaction can (e seen $ith penicillin therapy for
syphilis, riseofulvin or .etocona9ole therapy for dermatophyte infections, and
diethylcar(ama9ine therapy for oncocerciasis:
=verdosae is an e3aerated response to an increased amount of a medication: 4or e3ample,
increased doses of anticoaulants may result in purpura:
!hototo3ic dermatitis is an e3aerated sun(urn response caused (y the formation of to3ic
photoproducts, such as free radicals or reactive o3yen species +see Media file 10,:
Frequency
United #tate!
Dru eruptions occur in appro3imately 20AH of inpatients and in reater than 1H of outpatients:
Internationa
Dru eruptions occur in appro3imately 20;H of inpatients:
Mortaity.Mor"idity
Most dru eruptions are mild, self0limited, and usually resolve after the offendin aent has (een
discontinued: )evere and potentially life0threatenin eruptions occur in appro3imately 1 in 1000
hospital patients: Mortality rates for erythema multiforme +/M, ma<or are sinificantly hiher:
)tevens0%ohnson syndrome +)%), has a mortality rate of less than AH, $hereas the rate for 2/#
approaches 200;0H1 most patients die from sepsis:
#e/
Adverse cutaneous reactions to drus are more prevalent in $omen than in men:
Age
/lderly patients have an increased prevalence of adverse dru reactions:
)0INI)A0
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Hi!tory
2he first step is to revie$ the patientKs complete medication list, includin over0the0counter
supplements: Document any history of previous adverse reactions to drus or foods: *onsider
alternative etioloies, especially viral e3anthems and (acterial infections: /3anthematous
eruptions in children are more li.ely to (e due to a viral infection than another infection1
ho$ever, most such reactions in adults are due to medications:
#ote any concurrent infections, meta(olic disorders, or immunocompromise +e, due to H"5
infection, cancer, chemotherapy, (ecause these increase the ris. of dru eruptions:
"mmunocompromised persons have a 100fold hiher ris. of developin a dru eruption than the
eneral population: Althouh H"5 infection causes profound anery to other immune stimuli, the
fre8uency of dru hypersensitivity reactions, includin severe reactions +e, 2/#,, is mar.edly
increased in H"50positive individuals: !atients $ith advanced H"5 infection +*D@ count I200
cells?SL, have a 100 to A00fold increased ris. of developin an e3anthematous eruption to
sulfametho3a9ole:
#ote and detail the follo$in:
All prescription and over0the0counter drus, includin topical aents, vitamins, and
her(al and homeopathic remedies
2he interval (et$een the introduction of a dru and onset of the eruption
'oute, dose, duration, and fre8uency of dru administration
Use of parenterally administered drus, $hich are more li.ely than oral aents to cause
anaphyla3is
Use of topically applied drus, $hich are more li.ely than other drus to induce delayed0
type hypersensitivity reactions
Use of multiple courses of therapy and proloned administration of a dru, $hich can
cause alleric sensiti9ation
Any improvement after dru $ithdra$al and any reaction $ith readministration
&hy!ica
Althouh most dru eruptions are e3anthematous, different types of dru eruptions are descri(ed:
&ith every dru eruption, it is important to evaluate for certain clinical features that may
indicate a severe, potentially life0threatenin dru reaction, such as 2/# or
hypersensitivity syndrome: )uch features include the follo$in:

o Mucous mem(rane erosions

o 6listers +6listers herald a severe dru eruption:,
o #i.ols.y sin +epidermis slouhs $ith lateral pressure1 indicates serious eruption
that may constitute a medical emerency,
o *onfluent erythema
o Anioedema and tonue s$ellin
o !alpa(le purpura
o ).in necrosis +see Media file 2,
o Lymphadenopathy
o Hih fever, dyspnea, or hypotension
Appreciatin the morpholoy and features of dru eruptions is important: 2his can help
the clinician determine the causative medication and the most appropriate treatment:

o Acneiform: 2his is characteri9ed (y inflammatory papules or pustules that have a

follicular pattern: 2hey are locali9ed primarily on the upper (ody: "n contrast to
acne vularis, comedones are a(sent in acneiform eruptions:
o Acral erythema +erythrodysesthesia,: 2his is a relatively common reaction to
chemotherapy and is characteri9ed (y symmetric tenderness, edema, and
erythema of the palms and soles: "t is thouht to (e a direct to3ic effect on the
s.in: Acral erythema often resolves 20@ $ee.s after chemotherapy is discontinued:
o Acute enerali9ed e3anthematous pustulosis +A7/!,: Acute0onset fever and
enerali9ed scarlatiniform erythema occur $ith many small, sterile, nonfollicular
pustules: 2he clinical presentation is similar to pustular psoriasis, (ut A7/! has
more mar.ed hyperleu.ocytosis $ith neutrophilia and eosinophilia: Most cases
are caused (y drus +primarily anti(iotics, often in the first fe$ days of
administration: A fe$ cases are caused (y viral infections, mercury e3posure, or
U5 radiation: A7/! resolves spontaneously and rapidly, $ith fever and pustules
lastin 7010 days then des8uamation over a fe$ days:
o Dermatomyositisli.e: *utaneous findins include dermatomyositis +e, 7ottron
papules,, (ut patients tend to lac. muscle involvement, associated malinancy,
and antinuclear anti(odies: "mprovement is usually noted after the dru is
$ithdra$n:
o /M: 2his includes a spectrum of diseases +e, /M minor, /M ma<or,1 ho$ever,
many authorities cateori9e )%) and 2/# as /M ma<or and differentiate them (y
(ody surface involvement
o
/M minor 0 =verall, this is a mild disease1 patients are healthy: "t is
characteri9ed (y taret lesions distri(uted predominantly on the
e3tremities +see Media file E, Media file 22,: Mucous mem(rane
involvement may occur (ut is not severe: !atients $ith /M minor recover
fully, (ut relapses are common: Most cases are due to infection $ith
herpes simple3 virus, and treatment and prophyla3is $ith acyclovir is
helpful:
)%): 2his is characteri9ed (y $idespread s.in involvement, lare and
atypical taretoid lesions, sinificant mucous mem(rane involvement,
constitutional symptoms, and slouhin of 10H of the s.in: )%) can (e
caused (y drus and infections +especially those due to ycoplasma
pneumoniae,:
)%)?2/# overlap: /pidermal detachment involves 100;0H of (ody
surface area:
2/#: 2his is a severe s.in reaction that involves a prodrome of painful
s.in +not unli.e sun(urn, 8uic.ly follo$ed (y rapid, $idespread, full0
thic.ness s.in slouhin: "t typically affects ;0H or more the total (ody
surface area +see Media files ;0@,: )econdary infection and sepsis are
ma<or concerns, and pneumonia may develop from aspiration of slouhed
mucosa: Most cases are due to drus: 2he ris. of 2/# in H"50positive
patients is 10000fold hiher than in the eneral population:
o /rythema nodosum: 2his is characteri9ed (y tender, red, su(cutaneous nodules
that typically appear on the anterior aspect of the les: Lesions do not suppurate
or (ecome ulcerated +see Media file 1E,: "t is a reactive process often secondary to
infection, (ut it may (e due to medications, especially oral contraceptives and
sulfonamides:
o /rythroderma: 2his is $idespread inflammation of the s.in +see Media file A,, and
it may result from an underlyin s.in condition, dru eruption, internal
malinancy, or immunodeficiency syndrome: Lymphadenopathy is often noted,
and hepatosplenomealy, leu.ocytosis, eosinophilia, and anemia may (e present:
o 4i3ed dru eruptions: Lesions recur in the same area $hen the offendin dru is
iven +see Media file 7,: *ircular, violaceous, edematous pla8ues that resolve
$ith macular hyperpimentation is characteristic: Lesions occur ;0 minutes to F
hours after dru administration: !erioral and perior(ital lesions may occur, (ut the
hands, feet, and enitalia are the most common locations:
o Hypersensitivity syndrome: 2his is a potentially life0threatenin comple3 of
symptoms often caused (y anticonvulsants: !atients have fever, sore throat, rash,
lymphadenopathy, hepatitis, nephritis, and leu.ocytosis $ith eosinophilia: "t
usually (eins $ithin 10; $ee.s after a ne$ dru is started, (ut it may develop ;
months or later into therapy: Aromatic anticonvulsant drus cross0react +ie,
phenytoin, pheno(ar(ital, car(ama9epine,1 valproic acid is a safe alternative:
o Leu.ocytoclastic vasculitis: 2his is the most common severe dru eruption seen in
clinical practice +see Media file 11,: "t is characteri9ed (y (lanchin erythematous
macules 8uic.ly follo$ed (y palpa(le purpura: 4ever, myalias, arthritis, and
a(dominal pain may (e present: "t typically appears 7021 days after the onset of
dru therapy, and a la(oratory evaluation to e3clude internal involvement is
mandatory:
o Lichenoid: 2his reaction appears similar to lichen planus and may (e severely
pruritic +see Media file 12,: 2he eruption may include ec9ematous or psoriasiform
papules:
o Lupus: Dru0induced systemic lupus erythematosus +)L/, produces symptoms
identical to those of )L/, (ut s.in findins are uncommon: Lesions are also
identical to dru0induced su(acute cutaneous lupus erythematosus +)*L/,, $hich
is characteri9ed (y annular, psoriasiform, nonscarrin lesions in a
photodistri(uted pattern:
o Mor(illiform or e3anthematous: 2his is the most common pattern of dru
eruptions1 it is the 8uintessential dru rash: /3anthem is typically symmetric, $ith
confluent erythematous macules and papules that spare the palms and soles: "t
typically develops $ithin 2 $ee.s after the onset of therapy:
o !seudoporphyria: &hile larely a dru0induced condition, it can also occur $ith
use of tannin (eds and hemodialysis: !atients have (listerin and s.in fraility
that is clinically and patholoically +see Media file 20, identical to that of
porphyria cutanea tarda, (ut hypertrichosis and sclerodermoid chanes are a(sent
and urine and serum porphyrin levels are normal: 2reatment is sun protection and
$ithdra$al of the medication:
o )erum sic.ness and serum sic.nessDli.e: 2hese are type """ hypersensitivity
reactions mediated (y the deposition of immune comple3es in small vessels,
activation of complement, and recruitment of ranulocytes: *utaneous sins
typically (ein $ith erythema on the sides of the finers, hands, and toes and
proress to a $idespread eruption +most often mor(illiform or urticarial,: 5iscera
may (e involved, and fever, arthralia, and arthritis are common: )erum sic.nessD
li.e reactions have a clinical presentation similar to that of serum sic.ness
reactions, $ithout the immune comple3 deposition: 'enal involvement is rare:
)erum sic.nessDli.e reactions usually occur $ith anti(iotic therapy, especially
$ith cefaclor:
o )$eet syndrome +acute fe(rile neutrophilic dermatosis,: 2ender erythematous
papules and pla8ues occur most often on the face, nec., upper trun., and
e3tremities: 2he surface of the lesions may (ecome vesicular or pustular:
)ystemic findins are common and include fever +most often,, arthritis,
arthralias, con<unctivitis, episcleritis, and oral ulcers: La(oratory evaluation
usually reveals an elevated sedimentation rate, neutrophilia, and leu.ocytosis:
)$eet syndrome often occurs in association $ith cancers, inflammatory disorders,
prenancy, and medication use:
o Urticaria: 2his usually occurs as small $heals that may coalesce or may have
cyclical or yrate forms: Lesions usually appear shortly after the start of dru
therapy and resolve rapidly $hen the dru is $ithdra$n +see Media file 1F,: 7iant
urticaria is easily mista.en for /M:
o 5esiculo(ullous: 2hese reactions can resem(le pemphius, (ullous pemphioid,
linear immunolo(ulin A +"A, dermatosis, dermatitis herpetiformis, herpes
estationis, or cicatricial pemphioid: Most causative drus have a thiol roup,
disulfide (onds, or sulfur0containin rins that are meta(oli9ed to thiol forms:
2hiol0induced pemphius tends to resem(le pemphius foliaceus or pemphius
erythematosus1 nonthiol eruptions may resem(le pemphius vularis or
pemphius veetans: Mucosal findins may (e most common $ith nonthiol
drus: 'esults from direct and indirect immunofluorescence may (e positive in
persons $ith dru0induced pemphius and (ullous pemphioid: /ruptions usually
resolve after the inducin dru is discontinued, (ut D0penicillamineDinduced
pemphius may ta.e months to resolve and corticosteroids are often needed:
)au!e!
4i(rosin reactions have (een associated $ith a variety of chemical e3posures: #ephroenic
systemic fi(rosis has (een associated $ith adolinium contrast aents used for M'" studies:
"ndividuals $ith renal failure may have a (uildup adolinium in the s.in and other orans and
may recruit *D;@0positive (one marro$Dderived fi(rocytes into lesional areas: 2o3ic oil
inestion has (een associated $ith morphea, and 2e3ier disease has (een associated $ith
phytomenadione +vitamin0G1, in<ections:
'ates of reactions to commonly used drus

o Amo3icillin 0 A:1H
o 2rimethoprim sulfametho3a9ole 0 @:7H
o Ampicillin 0 @:2H
o )emisynthetic penicillin 0 2:BH
o 6lood +$hole human, 0 2:FH
o !enicillin 7 0 1:EH
o *ephalosporins 0 1:;H
o Ruinidine 0 1:2H
o 7entamicin sulfate 0 1H
o !ac.ed red (lood cells 0 0:FH
o Mercurial diuretics 0 0:BH
o Heparin 0 0:7H
*utaneous reaction rates in patients $ith H"5 infection

o )ulfasala9ine 0 20H
o 2rimethoprim0sulfametho3a9ole 0 1@:BH
o Dapsone 0 ;:1H
o Aminopenicillins 0 B:;H
o !enicillins 0 ;:FH
o Anticonvulsants 0 ;:@H
o !enicillinase0resistant penicillins 0 2:BH
o *ephalosporins 0 2:7H
o Ruinolones 0 2:1H
o Getocona9ole 0 2H
o *lindamycin 0 1:FH
o !rima8uine 0 1:FH
o 2etracycline 0 1:2H
o !entamidine 0 1H
o #)A"Ds 0 0:BH
o /rythromycin 0 0:EH
o Oidovudine 0 0:;H
Drus that commonly cause serious reactions

o Allopurinol
o Anticonvulsants
o #)A"Ds
o )ulfa drus
o 6umetanide
o *aptopril
o 4urosemide
o !enicillamine
o !iro3icam
o 2hia9ide diuretics
Drus unli.ely to cause s.in reactions

o Dio3in
o Meperidine
o Acetaminophen
o Diphenhydramine hydrochloride
o Aspirin
o Aminophylline
o !rochlorpera9ine
o 4errous sulfate
o !rednisone
o *odeine
o 2etracycline
o Morphine
o 'eular insulin
o &arfarin
o 4olic acid
o Methyldopa
o *hlorproma9ine
o )erotonin0specific reupta.e inhi(itors
Drus associated $ith specific morpholoic patterns: +#ote: 2he follo$in is a list of
medications that have (een reported to cause specific types of cutaneous reactions:
Ho$ever, not every possi(le type of dru eruption has (een listed: "n addition, e3clusion
of a dru from the follo$in list does not imply that it is not the cause of a patientKs
eruption: A hih inde3 of suspicion must al$ays (e maintained $hen confronted $ith a
ne$ onset eruption in a patient on multiple medications:,

o Acneiform 0 Amo3apine, corticosteroids +see Media file 1;,, haloens,

haloperidol, hormones, isonia9id, lithium, phenytoin, and tra9odone
o A7/! 0 Most commonly (eta0lactam anti(iotics, macrolides, and mercury1 less
commonly acetaminophen, allopurinol, (ufe3amac, (uphenine, car(ama9epine,
car(utamide, celeco3i(, chloramphenicol, clindamycin, co0trimo3a9ole,
clo(a9am, cyclins +e, tetracycline,, cytara(ine, diltia9em, famotidine,
furosemide, in.o (ilo(a, hydrochlorothia9ide, hydro3ychloro8uine, i(uprofen,
imatini(, imipenem, isonia9id, "5 contrast dye, lopinavir0ritonavir, me3iletine,
morphine, nado3olol, nifedipine, nystatin, olan9apine, phenytoin, pipemidic acid,
pipera9ine, pseudoephedrine, pyrimethamine, 8uinidine, ranitidine, rifampicin,
sal(utiamine, sertraline, simvastatin, streptomycin, ter(inafine, thallium, and
vancomycin
o Alopecia 0 A*/ inhi(itors, allopurinol, anticoaulants, a9athioprine,
(romocriptine, (eta0(loc.ers, cyclophosphamide, didanosine, hormones,
indinavir, #)A"Ds, phenytoin, methotre3ate +M2>,, retinoids, and valproate
o 6ullous pemphioid 0 Ampicillin, D0penicillamine, captopril, chloro8uine,
ciproflo3acin, enalapril, furosemide, neuroleptics, penicillins, phenacetin,
psoralen plus U50A, salicyla9osulfapyridine, sulfasala9ine, and ter(inafine
o Dermatomyositisli.e 0 6*7 vaccine, hydro3yurea +most common,, lovastatin,
omepra9ole, penicillamine, simvastatin, and teafur
o /rythema nodosum 0 /chinacea, haloens, oral contraceptives +most common,,
penicillin, sulfonamides, and tetracycline
o /rythroderma 0 Allopurinol, anticonvulsants, aspirin, (ar(iturates, captopril,
car(ama9epine, cefo3itin, chloro8uine, chlorproma9ine, cimetidine, diltia9em,
riseofulvin, lithium, nitrofurantoin, omepra9ole, phenytoin, )t: %ohnKs $ort,
sulfonamides, and thalidomide
o 4i3ed dru eruptions 0 Acetaminophen, ampicillin, anticonvulsants,
aspirin?#)A"D, (ar(iturates, (en9odia9epines, (utal(ital, cetiri9ine, ciproflo3acin,
clarithromycin, dapsone, de3tromethorphan, do3ycycline, flucona9ole,
hydro3y9ine, lamotriine, loratadine, metronida9ole, oral contraceptives,
penicillins, phenacetin, phenolphthalein, phenytoin, piro3icam, sa8uinavir,
sulfonamides, tetracyclines, ticlopidine, tolmetin, vancomycin, and 9olmitriptan
o Hypersensitivity syndrome 0 Allopurinol, amitriptyline, car(ama9epine, dapsone,
lamotriine, minocycline, #)A"Ds, olan9apine, o3car(a9epine, pheno(ar(ital,
phenytoin, sa8uinavir, spironolactone, sulfonamides, 9alcita(ine, and 9idovudine
o Lichenoid 0 Amlodipine, antimalarials, (eta0(loc.ers, captopril, diflunisal,
diltia9em, enalapril, furosemide, limepiride, old, leflunomide, levamisole, L0
thyro3ine, orlistat, penicillamine, phenothia9ine, pravastatin, proton pump
inhi(itors, rofeco3i(, salsalate, sildenafil, tetracycline, thia9ides, and
ursodeo3ycholic acid
o Linear "A dermatosis 0 Atorvastatin, captopril, car(ama9epine, diclofenac,
li(enclamide, lithium, phenytoin, and vancomycin
o Lupus erythematosus
o
Dru0induced )L/ is most commonly associated $ith hydrala9ine,
procainamide, and minocycline: 6eta0(loc.ers, chlorproma9ine,
cimetidine, clonidine, estroens, isonia9id, lithium, lovastatin,
methyldopa, oral contraceptives, 8uinidine, sulfonamides, tetracyclines,
and tumor necrosis factor +2#4,Dalpha inhi(itors have (een reported:
Dru0induced )*L/ is most commonly associated $ith
hydrochlorothia9ide: *alcium channel (loc.ers, cimetidine, riseofulvin,
leflunomide, ter(inafine, and 2#40alpha inhi(itors have (een reported:
o Mor(illiform +e3anthematous, 0 A*/ inhi(itors, allopurinol, amo3icillin,
ampicillin, anticonvulsants, (ar(iturates, car(ama9epine, cetiri9ine, in.o (ilo(a,
hydro3y9ine, isonia9id, nelfinavir, #)A"Ds, phenothia9ine, phenytoin,
8uinolones, sulfonamides, thalidomide, thia9ides, trimethoprim0sulfametho3a9ole,
and 9alcita(ine
o !emphius
o
2hiols include captopril, D0penicillamine, old sodium thiomalate,
mercaptopropionyllycine, pyritinol, thiama9ole, and thiopronine:
#onthiols include aminophena9one, aminopyrine, a9apropa9one,
cephalosporins, heroin, hydantoin, imi8uimod, indapamide, levodopa,
lysine acetylsalicylate, montelu.ast, o3yphen(uta9one, penicillins,
pheno(ar(ital, phenyl(uta9one, piro3icam, proesterone, propranolol, and
rifampicin:
o !hotosensitivity 0 A*/ inhi(itors, amiodarone, amlodipine, celeco3i(,
chlorproma9ine, diltia9em, furosemide, riseofulvin, lovastatin, nifedipine,
phenothia9ine, piro3icam, 8uinolones, sulfonamides, tetracycline, and thia9ide
o !seudoporphyria 0 Amiodarone, (umetanide, chlorthalidone, cyclosporine,
dapsone, etretinate, A0fluorouracil, flutamide, furosemide,
hydrochlorothia9ide?triamterene, isotretinoin, #)A"Ds +includin nalidi3ic acid
and napro3en,, oral contraceptive pills, and tetracycline
o !soriasis 0 A*/ inhi(itors, aniotensin receptor antaonists, antimalarials, (eta0
(loc.ers, (upropion, calcium channel (loc.ers, car(ama9epine, interferon +"4#,
alfa, lithium, metformin, #)A"Ds, ter(inafine, tetracyclines, valproate sodium,
and venlafa3ine
o )erum sic.ness 0 Antithymocyte lo(ulin for (one marro$ failure, human ra(ies
vaccine, penicillin, pneumococcal vaccine +in A"D) patients,, and vaccines
containin horse serum derivatives
o )erum sic.nessDli.e 0 6eta0lactam anti(iotics, cefaclor +most common,,
minocycline, propranolol, strepto.inase, sulfonamides, and #)A"Ds
o )%) 0 Allopurinol, anticonvulsants, aspirin?#)A"D), (ar(iturates, car(ama9epine,
cimetidine, ciproflo3acin, codeine, didanosine, diltia9em, erythromycin,
furosemide, riseofulvin, hydantoin, indinavir, nitroen mustard, penicillin,
phenothia9ine, phenyl(uta9one, phenytoin, ramipril, rifampicin, sa8uinavir,
sulfonamides, tetracyclines, and trimethoprim0sulfametho3a9ole
o )$eet syndrome 0 All0trans0retinoic acid, celeco3i(, ranulocyte colony0
stimulatin factor, nitrofurantoin, oral contraceptives, tetracyclines, and
trimethoprim0sulfametho3a9ole
o 2/# 0 Alfu9osin, allopurinol, anticonvulsants, aspirin?#)A"Ds, sulfado3ine and
pyrimethamine +4ansidar,, isonia9id, lamotriine, lansopra9ole, letro9ole,
penicillins, phenytoin, pra9osin, sulfonamides, tetracyclines, thalidomide,
trimethoprim0sulfametho3a9ole, and vancomycin
o Urticaria 0 A*/ inhi(itors, alendronate, aspirin?#)A"Ds, (lood products,
cephalosporins, cetiri9ine, clopidorel, de3tran, didanosine, infli3ima(, inhaled
steroids, nelfinavir, opiates, penicillin, peptide hormones, polymy3in, proton
pump inhi(itors, radioloic contrast material, ranitidine, tetracycline, vaccines,
and 9idovudine
o 5asculitis 0 Adalimuma(, allopurinol, aspirin?#)A"Ds, cimetidine, old,
hydrala9ine, indinavir, leflunomide, levoflo3acin, minocycline, montelu.ast,
penicillin, phenytoin, propylthiouracil, proton pump inhi(itors, 8uinolones,
ramipril, sulfonamide, tetracycline, thia9ides, and thiorida9ine
o 5esiculo(ullous +other, 0 A*/ inhi(itors, aspirin?#)A"Ds, (ar(iturates, captopril,
cephalosporins, entacapone, estroen, furosemide, riseofulvin, influen9a vaccine,
penicillamine, penicillins, sertraline sulfonamides, and thia9ides
!sychotropic drus associated $ith specific morpholoic patterns

o Alopecia 0 *ar(ama9epine, fluo3etine, lamotriine, lithium, a(apentin, and

valproic acid
o /M 0 6ar(iturates, car(ama9epine, dia9epam overdose, fluo3etine, a(apentin,
lithium plus tra9odone concurrently, pheno(ar(ital, risperidone, sertraline, and
valproic acid
o Mor(illiform +e3anthematous, 0 Alpra9olam, (ar(iturates, (upropion,
car(ama9epine, chlorproma9ine, desipramine, fluo3etine, lithium, maprotiline,
nefa9odone, risperidone, and tra9odone
o !hotosensitivity 0 All antipsychotics, (ar(iturates, car(ama9epine,
chlorproma9ine, do3epin, imipramine, thiorida9ine, and valproic acid
o !imentation 0 Amitriptyline, car(ama9epine, chlorproma9ine, clo9apine,
dia9epam follo$in derma(rasion, a(apentin, haloperidol, lamotriine,
perphena9ine, and thiorida9ine
o Urticaria 0 6upropion, car(ama9epine, chlordia9epo3ide, fluo3etine, imipramine,
lamotriine, lithium, paro3etine, and tra9odone
o 5asculitis 0 4luo3etine, maprotiline, paro3etine, and tra9odone
*hemotherapeutic aents associated $ith specific morpholoic patterns

o Acneiform 0 *etu3ima(, dactinomycin, erlotini(, fluo3ymesterone, efitini(,

medro3yproesterone, and vin(lastine
o Acral erythema +erythrodysesthesia, 0 *apecita(ine, cisplatin, clofara(ine,
cyclophosphamide, cytara(ine, doceta3el, do3oru(icin, fluorouracil, emcita(ine,
M2>, teafur, and vinorel(ine
o Alopecia
o
All classes of chemotherapeutic aents are associated $ith alopecia:
*ommonly associated drus include al.ylatin aents, anthracyclines,
(leomycin, do3oru(icin, hydro3yurea, M2>, mitomycin, mito3antrone,
vin(lastine, and vincristine:
6usulfan and cyclophosphamide administered in com(ination can cause
permanent hair loss:
o /M 0 6usulfan, chloram(ucil, cyclophosphamide, diethylstil(estrol +D/),,
etoposide, hydro3yurea, mechlorethamine, M2>, mitomycin *, mitotane,
paclita3el, and suramin
o /rythema nodosum 0 6usulfan, D/), and imatini(
o 4i3ed dru eruptions 0 Dacar(a9ine, hydro3yurea, paclita3el, and procar(a9ine
o Hyperpimentation 0 6ischloroethylnitrosourea +6*#U1 carmustine,, (leomycin,
(usulfan, (re8uinar, cisplatin, cyclophosphamide, dactinomycin, daunoru(icin,
doceta3el, do3oru(icin, fluorouracil, fotemustine, hydro3yurea, ifosfamide, M2>,
mithramycin, mito3antrone, nitroen mustard, procar(a9ine, teafur, thiotepa, and
vinorel(ine
o Lichenoid 0 Hydro3yurea, imatini(, and teafur
o Lupus 0 Aminolutethimide, D/), hydro3yurea, leuprolide, and teafur
o Mor(illiform +e3anthematous, 0 6leomycin, car(oplatin, cis0dichloro0trans0
dihydro3y0bis0isopropylamine platinum +*H"!,, chloram(ucil, cytara(ine,
doceta3el, D/), do3oru(icin, etoposide, A0fluorouracil, hydro3yurea, M2>,
mitomycin *, mitotane, mito3antrone, paclita3el, pentostatin, procar(a9ine,
suramin, and thiotepa
o 2/# 0 Asparainase, (leomycin, chloram(ucil, cladri(ine, cytara(ine,
do3oru(icin, A0fluorouracil, M2>, plicamycin, procar(a9ine, and suramin
o Urticaria 0 Amsacrine, (leomycin, (usulfan, car(oplatin, chloram(ucil, cisplatin,
cyclophosphamide, cytara(ine, daunoru(icin, dia9i8uone, didemnin, D/),
doceta3el, do3oru(icin, epiru(icin, etoposide, A0fluorouracil, mechlorethamine,
melphalan, M2>, mitomycin *, mitotane, mito3antrone, paclita3el, pentostatin,
procar(a9ine, teniposide, thiotepa, trimetre3ate, vincristine, and 9inostatin
o 5asculitis 0 6usulfan, cyclophosphamide, cytara(ine, he3amethylene
(isacetamide +HM6A,, hydro3yurea, imatini(, levamisole, E0mercaptopurine,
M2>, mito3antrone, ritu3ima(, and tamo3ifen
*utaneous reactions to cyto.ine therapy

o /rythropoietin 0 A(normal hair ro$th, locali9ed rash, palpe(ral edema, and

$idespread ec9ema
o 7ranulocyte colony stimulatin factor 0 /3acer(ation of pree3istin psoriasis,
leu.ocytoclastic, locali9ed erythema, locali9ed pruritus, )$eet syndrome, and
vasculitis
o 7ranulocyte macrophae colony0stimulatin factor 0 Alopecia, epidermolysis,
e3acer(ation of vasculitis, e3foliative dermatitis, flushin, locali9ed erythema,
locali9ed $heals, maculopapular eruptions, pruritus, purpura, and urticaria
o "4#0alfa 0 Alopecia, anasarca, cutaneous vascular lesions, eosinophilic fasciitis,
e3acer(ation of pree3istin herpes la(ialis, facial erythema, fi3ed dru eruption,
hyperpimentation, nummular ec9ema, paraneoplastic pemphius, pruritus,
psoriasis, sarcoidosis, )L/, urticaria, and 3erostomia
o "4#0(eta 0 4atal pemphius vularis +$hen used in com(ination $ith interleu.in
+"L,D2, locali9ed reactions +common,, and urticaria
o "4#0amma 0 "ncreased relapses in melanoma and locali9ed inflammation
o "L01alpha 0 Mucositis, phle(itis, )h$art9man reaction, and 3erostomia
o "L01(eta 0 /rythema at surical $ound sites, phle(itis, and rash
o "L02 0 6listers, cutaneous ulcers, des8uamation, erythema, erythema nodosum,
erythroderma, e3acer(ation of autoimmune s.in disorders, flushin,
hypersensitivity to iodine contrast material, necrosis, pruritus, teloen effluvium,
2/#, and urticaria
o "L0; 0 4acial flushin, hemorrhaic rash, throm(ophle(itis, and urticaria
o "L0@ 0 4acial and peripheral edema, 7rover disease, and papular rash
o "L0E 0 Diffuse erythematous scalin macules and papules
o 2#40alpha 0 /rythroderma and locali9ed erythema
DIFFERENTIA0#
)ection @ of 11
Authors and /ditors
"ntroduction
*linical
Differentials
&or.up
2reatment
Medication
4ollo$0up
Miscellaneous
Multimedia
'eferences
Acute 4e(rile #eutrophilic Dermatosis
*ontact Dermatitis, Alleric
*ontact Dermatitis, "rritant
/rythema Multiforme
/rythema #odosum
/rythroderma +7enerali9ed /3foliative Dermatitis,
7ianotti0*rosti )yndrome +!apular Acrodermatitis of *hildhood,
7raft 5ersus Host Disease
Hypersensitivity 5asculitis +Leu.ocytoclastic 5asculitis,
Lichen !lanus
Measles, 'u(eola
!ityriasis 'osea
!orphyria *utanea 2arda
!soriasis, !ustular
'u(ella
)yphilis
Urticaria, Acute
Urticaria, *hronic
Other &ro"em! to "e )on!idered
Autoimmune (listerin disease
/3acer(ation of pree3istin cutaneous disease
"nfection +viral Mmost commonN, (acterial, funal,
WORKU&
)ection A of 11
Authors and /ditors
"ntroduction
*linical
Differentials
&or.up
2reatment
Medication
4ollo$0up
Miscellaneous
Multimedia
'eferences
0a" #tudie!
History and physical e3amination are often sufficient for dianosin mild asymptomatic
eruptions:
)evere or persistent eruptions may re8uire further dianostic testin:

o 6iopsy can (e helpful in confirmin the dianosis of a dru eruption +e, (y

sho$in eosinophils in mor(illiform eruptions or numerous neutrophils $ithout
vasculitis in persons $ith )$eet syndrome,:
o *6* count $ith differential may sho$ leu.openia, throm(ocytopenia, and
eosinophilia in patients $ith serious dru eruptions:
o )erum chemistry studies may (e useful: Liver involvement leadin to death can
occur in persons $ith hypersensitivity syndromes: )pecial attention should (e
paid to the electrolyte (alance and renal and?or hepatic function indices in patients
$ith severe reactions such as )%), 2/#, or vasculitis:
o Anti(ody and?or immunoseroloy tests may (e ordered: Antihistone anti(odies
are noted in persons $ith dru0induced )L/, $hereas anti0'o?))0A anti(odies are
most common in persons $ith dru0induced )*L/:
o Direct cultures may (e needed to investiate a primary infectious etioloy or
secondary infection:
o Urinalysis, stool uaiac tests, and chest radioraphy are important for patients
$ith vasculitis:
Imaging #tudie!
*hest radioraphy, alon $ith urinalysis and stool uaiac tests, is important for patients
$ith vasculitis:
Other Te!t!
'echallene tests (y means of s.in pric. or patch testin to confirm the causative aent is
of limited value:
).in tests may (e ha9ardous to patients $ho have had severe reactions:
&ith the possi(le e3ception of A7/!, patch tests have a lo$ sensitivity and specificity
and are not useful:
Hi!toogic Finding!
"n some cases, (iopsy may (e helpful in esta(lishin a dianosis of a dru reaction:
Histopatholoy of an e3anthematous dru eruption may sho$ (oth superficial and deep
perivascular inflammatory cell infiltrates: /osinophils in the infiltrate suest such a dru
eruption +see Media file 21,:
"n patients $ith )$eet syndrome, (iopsy reveals edema of the superficial dermis and a dense
infiltrate of neutrophils: Leu.ocytoclasia may (e present, (ut vasculitis is a(sent:
Histopatholoy of 2/# sho$s su(epidermal split, full0thic.ness epidermal necrosis and a sparse
perivascular lymphocytic infiltrate +see Media file 20,:
TREATMENT
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Medica )are
2he ultimate oal is al$ays to discontinue the offendin medication if possi(le:
"ndividuals $ith dru eruptions are often the most ill patients ta.in the most
medications, many of $hich are essential for their survival: Ho$ever, all nonessential
medications should (e limited: =nce the offendin dru has (een identified, it should (e
promptly discontinued: Gno$lede of the common eruption inducinDmedications may
help in identifyin the offendin dru:
!atients can possi(ly continue to (e treated throuh mor(illiform eruptions +ie, continue
medication even in patients $ith a rash,: 2he eruption often resolves, especially if the
individual is (ein treated $ith antihistamines: Most authorities (elieve that
e3anthematous dru eruptions are not a precursor to severe reactions, such as 2/#:
#evertheless, all patients $ith severe mor(illiform eruptions should (e monitored for
mucous mem(rane lesions, (listerin, and s.in slouhin:
2reatment of a dru eruption depends on the specific type of reaction: 2herapy for
e3anthematous dru eruptions is supportive in nature: 4irst0eneration antihistamines are
used 2@ h?d: Mild topical steroids +e, hydrocortisone, desonide, and moisturi9in lotions
are also used, especially durin the late des8uamative phase:
)evere reactions, such as )%), 2/#, and hypersensitivity reactions, $arrant hospital
admission: 2/# is (est manaed in a (urn unit $ith special attention iven to electrolyte
(alance and sins of secondary infection: 6ecause adhesions can develop and result in
(lindness, evaluation (y an ophthalmoloist is mandatory: "n addition, mountin
evidence indicates that intravenous immunolo(ulin +"5"7, may improve outcomes for
2/# patients:
Hypersensitivity syndrome, a systemic reaction characteri9ed (y fever, sore throat, rash,
and internal oran involvement, is potentially life threatenin: 2imely reconition of the
syndrome and immediate discontinuation of the anticonvulsant or other offendin dru
are crucial: !atients may re8uire liver transplantation if the dru is not stopped in time:
2reatment $ith systemic corticosteroids has (een advocated:
MEDI)ATION
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2herapy for most dru eruptions is mainly supportive in nature: Mor(illiform eruptions are
treated $ith oral antihistamines and topical steroids: "5"7 is currently the most common aent
used to treat 2/#: *yclosporine may also have a role in the treatment of 2/#: !rednisone may
(e used in the treatment of hypersensitivity syndrome $ith heart and lun involvement, severe
serum sic.nessDli.e reaction, and )$eet syndrome:
Drug )ategory+ First-generation antihistamines
2hese aents antaoni9e H1 receptors and (loc. release of histamine: 2hey provide symptomatic
relief of pruritus and help improve eruptions:
Drug Name
Hydro3y9ine H*l +An3anil, Atara3, Ato9ine,
Durra3, 5istaril,
De!cri-tion
Antaoni9es H1 receptors in periphery: May
suppress histamine activity in su(cortical *#):
Availa(le as 100, 2A0, A00, or 1000m ta(:
Adut Do!e 2A m != 8Eh
&ediatric Do!e 10 m?A mL syr, 0:A01 m?.?d != 8id
)ontraindication! Documented hypersensitivity
Interaction!
*#) depression may increase $ith alcohol or other
*#) depressants +e, meperidine, (ar(iturates,
&regnancy
* 0 )afety for use durin prenancy has not (een
esta(lished:
&recaution! *linical e3acer(ations of porphyria +may not (e
safe in porphyria,1 /*7 a(normalities +alterations
in 2 $aves, may occur1 may cause dro$siness1 not
recommended in early prenancy or (reastfeedin
Drug Name
Diphenhydramine H*l +6enadryl, 6enylin,
Diphen, AllerMa3,
De!cri-tion
4or symptomatic relief of alleric symptoms
caused (y release of histamine in immune
reactions:
Adut Do!e 2A0A0 m ta( != 8@0Eh
&ediatric Do!e 12:A m?A mL syr, A m?.?d != divided 8@0Eh
)ontraindication! Documented hypersensitivity1 MA="s
Interaction!
!otentiates effect of *#) depressants1 (ecause of
alcohol content, do not administer syr form to
patient ta.in medications that can cause
disulfiramli.e reactions
&regnancy
* 0 )afety for use durin prenancy has not (een
esta(lished:
&recaution!
May e3acer(ate anle0closure laucoma,
hyperthyroidism, peptic ulcer, and urinary tract
o(struction
Drug )ategory+ Second-generation antihistamines, nonsedating
2hese aents cause less, if any, dro$siness than first0eneration aents:
Drug Name Loratadine +*laritin,
De!cri-tion
)electively inhi(its peripheral histamine H1
receptors:
Adut Do!e 10020 m != 8d
&ediatric Do!e
I2 years: #ot esta(lished
20E years: A m != 8d
JE years: Administer as in adults
)ontraindication! Documented hypersensitivity
Interaction!
Getocona9ole, erythromycin, procar(a9ine, and
alcohol may increase levels
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution!
)tart at lo$ dose in renal and liver impairment1
caution in (reastfeedin
Drug )ategory+ Corticosteroids
2opical aents provide symptomatic relief of pruritus: )ystemic steroids are used in persons $ith
hypersensitivity syndrome, severe serum sic.nessDli.e reactions, and )$eet syndrome:
Drug Name Desonide 0:0AH cream, ointment, lotion
De!cri-tion
4or inflammatory dermatosis responsive to
steroids1 decreases inflammation (y suppressin
miration of !M# leu.ocytes and reversin
capillary permea(ility:
Adut Do!e Apply sparinly 20@ times?d
&ediatric Do!e Apply as in adults
)ontraindication!
Documented hypersensitivity1 funal, viral, and
(acterial s.in infections
Interaction! #one reported
&regnancy
* 0 )afety for use durin prenancy has not (een
esta(lished:
&recaution!
!roloned use, application over lare surface areas,
application of potent steroids, and occlusive
dressins may increase systemic a(sorption and
may result in *ushin syndrome, reversi(le H!A0
a3is suppression, hyperlycemia, and lycosuria
Drug Name !rednisone +Deltasone, =rasone, )terapred,
De!cri-tion
"mmunosuppressant for treatment of immune
disorders1 may decrease inflammation (y reversin
increased capillary permea(ility and suppressin
!M# activity1 availa(le in 2:A0, A0, 100, 200, or A00
m ta(:
Adut Do!e 102 m?. != 8d initially, taper over @0E $.
&ediatric Do!e
102 m?. != 8d or divided (id?8id1 taper over 2
$. as symptoms resolve
)ontraindication!
A(solute: )ystemic funal infection, herpes
simple3 .eratitis, hypersensitivity +usually $ith
corticotropin (ut occasionally noted $ith "5
preparations,
'elative: hypertension, active tu(erculosis,
conestive heart failure, prior psychosis, positive
intradermal positive protein derivative te3t,
laucoma, severe depression, dia(etes mellitus,
active peptic ulcer disease, cataracts, osteoporosis,
recent (o$el anastomosis, prenancy
Interaction! *oadministration $ith estroens may decrease
clearance1 $hen used $ith dio3in, diitalis
to3icity secondary to hypo.alemia may increase1
pheno(ar(ital, phenytoin, and rifampin may
increase meta(olism of lucocorticoids +consider
increasin maintenance dose,1 monitor for
hypo.alemia $ith coadministration of diuretics
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution!
A(rupt discontinuation may cause adrenal crisis1
hyperlycemia, edema, osteonecrosis, myopathy,
peptic ulcer disease, hypo.alemia, osteoporosis,
euphoria, psychosis, myasthenia ravis, ro$th
suppression, and infections may occur
Drug )ategory+ Immunoglobulins
2hese aents are used to treat 2/#:
Drug Name
"ntravenous immunolo(ulin +7ammaard,
7amimune,
De!cri-tion
6lood product prepared from pooled plasma of
healthy donors: 4ollo$in features are possi(ly
relevant to efficacy: neutrali9ation of circulatin
myelin anti(odies throuh anti0idiotypic
anti(odies1 do$n0reulation of proinflammatory
cyto.ines, includin "4#0amma1 (loc.ade of 4c
receptors on macrophaes1 suppression of inducer
2 and 6 cells and aumentation of 20suppressor
cells1 (loc.ade of complement cascade1 promotion
of remyelination1 and 10H increase in *)4 "7:
Adut Do!e 1 ?. "5 8d for ; consecutive days
&ediatric Do!e Administer as in adults
)ontraindication!
Documented hypersensitivity1 "A deficiency1 anti0
"/?"7 anti(odies
Interaction! #one reported
&regnancy
6 0 Usually safe (ut (enefits must out$eih the
ris.s:
&recaution! *onsider chec.in serum "A level (efore therapy
and usin "A0depleted "5"7 +707ard0)D, if
indicated1 may increase serum viscosity and
throm(oem(olic events1 miraine headache
reported1 10H increased ris. of aseptic meninitis1
increased ris. of urticaria, pruritus, or petechiae 20
A d after infusion, $hich may last I1 mo1 increased
ris. of renal tu(ular necrosis in elderly persons,
dia(etes, volume depletion, or pree3istin .idney
disease1 can alter la(oratory values +e, elevated
antiviral or anti(acterial anti(ody titers for 1 mo,
E0fold increase in /)' for 20; $.,1 apparent
hyponatremia
FO00OW1U&
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&rogno!i!
4ull recovery $ithout any complications is e3pected for most dru eruptions:
/ven after the responsi(le aent is discontinued, dru eruptions may clear slo$ly or
$orsen over the ne3t fe$ days: 2he time re8uired for total clearin may (e 102 $ee.s or
loner:
!atients $ith e3anthematous eruptions should (e counseled to e3pect mild des8uamation
as the rash resolves:
!atients $ith hypersensitivity syndrome are at ris. of (ecomin hypothyroid, usually
$ithin the first @012 $ee.s after the reaction:
2he pronosis for patients $ith 2/# is uarded: )carrin, (lindness, and death are
possi(le:
&atient Education
"f the responsi(le dru is identified, advise the patient to avoid that dru in the future:
*learly la(el the medical record: Advise patients to carry a card or some other form of
emerency identification in their $allets that lists dru alleries and?or intolerances,
especially if they have had a severe reaction:
Advise patients a(out drus that are cross0reactive and a(out drus that must (e avoided:
4or e3ample, penicillin allery reactions have cross0reactivity $ith cephalosporins,
phenytoin hypersensitivity syndrome has cross0reactivity $ith pheno(ar(ital and
car(ama9epine, and sulfonamide reactions cross0react $ith other sulfa0containin drus:
4or e3cellent patient education resources, visit eMedicineKs Allery *enter: Also, see
eMedicineKs patient education article Dru Allery:
MI#)E00ANEOU#
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Medica.0ega &it3a!
Dru reactions are a common reason for litiation: #ot $arnin a patient a(out potential
adverse effects, prescri(in a medicine to a previously sensiti9ed patient, and prescri(in
a related medication $ith cross0reactivity are the most common medicoleal pitfalls:
4ailure to dianose a reaction to medication may prompt litiation: "f anticonvulsant
hypersensitivity is not reconi9ed early and the dru is not $ithdra$n promptly, death or
liver failure may result:
/arly reconition, transfer to a (urn unit, and possi(ly "5"7 may decrease the mortality
and mor(idity of )%) and 2/#:
MU0TIMEDIA
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Media file 1: Mor"ii3orm drug eru-tion4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 2: War3arin 5)oumadin6 necro!i! in7o7ing the eg4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file ;: To/ic e-iderma necroy!i!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file @: #te7en!1'ohn!on !yndrome4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file A: Erythroderma4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file E: Erythema muti3orme4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 7: Fi/ed drug eru-tion4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file F: Fi/ed drug eru-tion in7o7ing the -eni!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file B: Ora uceration! in a -atient recei7ing cytoto/ic thera-y4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 10: &hototo/ic reaction a3ter u!e o3 a tanning "ooth4 Note !har- cuto33 $here
cothing "oc(ed e/-o!ure4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 11: 2a!cuitic reaction on the eg!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 12: 0ichen -anu! on the nec(4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1;: #teroid acne4 Note -u!tue! and a"!ence o3 comedone!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1@: Drug reaction to hydro/ychoroquine 5&aqueni64
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1A: Urticaria4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1E: Erythema nodo!um4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 17: )on3uent necro!i! o3 the e-idermi! in to/ic e-iderma necroy!i!4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1F: &eri7a!cuar mi/ed in3ammatory in3itrate $ith eo!ino-hi!
characteri!tic o3 drug1induced urticaria4
5ie$ 4ull )i9e "mae
Media type: !hoto
Media file 1B: ,io-!y o3 -!eudo-or-hyria !ho$! a !u"e-iderma "i!ter $ith itte to no
in3ammation4
5ie$ 4ull )i9e "mae
Media type: "mae
Media file 20: )on3uent necro!i! o3 the e-idermi! in to/ic e-iderma necroy!i!4
5ie$ 4ull )i9e "mae
Media type: "mae
Media file 21: #u-er3icia -eri7a!cuar in3ammatory in3itrate $ith numerou!
eo!ino-hi! characteri!tic o3 an e/anthematou! drug eru-tion4
5ie$ 4ull )i9e "mae
Media type: "mae
Media file 22: Target e!ion! o3 erythema muti3orme4
5ie$ 4ull )i9e "mae
Media type: "mae
REFEREN)E#
)ection 11 of 11
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Angioedema
+redirected from ;uinc5e<s oe!ema,
anioedema ?an\io\ede\ma? +0e0de]mah, a vascular reaction involvin the deep
dermis or su(cutaneous or su(mucosal tissues, representin locali9ed edema caused (y
dilatation and increased permea(ility of the capillaries, and characteri9ed (y the development of
iant $heals:
hereditary angioedema an autosomal dominant disorder of *1 inhi(itor +*1 "#H,, $hich
causes uncontrolled activation of the classical complement path$ay, manifested as recurrent
episodes of edema of the s.in and upper respiratory and astrointestinal tracts $ith increased
levels of several vasoactive mediators of anaphyla3is: "t may (e mediated (y such factors as
minor trauma, sudden chanes in environmental temperature, and sudden emotional stress:
DorlandKs Medical Dictionary for Health *onsumers: ^ 2007 (y )aunders, an imprint of
/lsevier, "nc: All rihts reserved:
2he American Heritae_ Medical Dictionary *opyriht ^ 2007, 200@ (y Houhton Mifflin
*ompany: !u(lished (y Houhton Mifflin *ompany: All rihts reserved:
Anioedema
An alleric s.in disease characteri9ed (y patches of confined s$ellin involvin the s.in the
layers (eneath the s.in, the mucous mem(ranes, and sometimes the viscera`called also
anioneurotic edema, iant urticaria, Ruinc.eKs disease, or Ruinc.eKs edema:
Mentioned in: Alleries, Antihypertensive Drus
7ale /ncyclopedia of Medicine: *opyriht 200F 2he 7ale 7roup, "nc: All rihts reserved:
anioedema +anioneurotic edema, Ruinc.eKs disease, +an]<ab da]m ,,
n the spontaneous s$ellin of the lips, chee.s, eyelids, tonue, soft palate, pharyn3, and lottis,
fre8uently associated $ith allery to food or drus and lastin from several hours to several
days: "nvolvement of the lottis results in o(struction of the air$ay:
Anioedema:
Mos(yKs Dental Dictionary, 2nd edition: ^ 200F /lsevier, "nc: All rihts reserved:
anioedema
a condition characteri9ed (y the sudden and temporary appearance of lare areas of painless
s$ellin in the su(cutaneous tissue or su(mucosa, $ith or $ithout pruritus: *aused (y
immunoloical reactions, usually immediate type hypersensitivities: )ometimes referred to as
anioneurotic edema:
hereditary angioedema
in humans, the periodic occurrence of anioedema caused (y a deficiency of the complement
reulatory protein:
)aunders *omprehensive 5eterinary Dictionary, ; ed: ^ 2007 /lsevier, "nc: All rihts
reserved
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