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Abstract
The medical records and histopathological sections
of 29 dogs diagnosed with a unique eosinophilic dermatitis resembling Wells syndrome were reviewed
in an attempt to elucidate the pathogenesis of this
syndrome. The medical records were reviewed for
information on dermatological lesion appearance, systemic signs in other organ systems, clinical analyte
abnormalities, and drug therapy. Histological sections
of dogs with moderate to severe eosinophilic dermatitis
without folliculitis and furunculosis were reviewed
and evaluated for the presence of collagen flame figures.
Three categories of patients were found. Category 1
consisted of 17 dogs treated for vomiting and/or diarrhoea (often haematochezia or haematemesis) prior
(mean: 4.6 days) to the onset of skin lesions. Fourteen
category 1 dogs had erythematous lesions (macules,
papules or plaques) that were most pronounced on
the abdomen. Sixteen of the 17 dogs received multiple
classes of drugs, and 59% were hypoalbuminemic.
Category 2 consisted of five dogs that had skin lesions
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Introduction
A unique eosinophilic dermatitis was originally described
in nine dogs at the Matthew J. Ryan Veterinary Teaching
Hospital of the University of Pennsylvania. This disorder
was characterized by an erythematous maculopapular
eruption with marked eosinophilic inflammation, collagen
flame figures and dermal oedema. This disorder was
thought to be similar to eosinophilic cellulitis in humans,
also known as Wells syndrome. All dogs had bright red
papules or plaques on the ventral abdomen, thorax, and
pinnae that often developed from erythematous macules
with central clearing. The stimuli that preceded the
development of lesions included arthropod bites, food
hypersensitivity, drug (metronidazole) and allergic skin
disease.1
In humans, Wells syndrome is a clinical entity diagnosed
by the clinical presentation, disease course, and histological
features. Affected people may develop prodromal pruritus
or burning followed by annular areas of erythema, blisters
or urticaria. The lesions progress to form large, painful, and
often recurrent, erythematous plaques that may have a
rosy to violaceous hue and central clearing. The swellings
resemble infectious cellulitis but do not respond to antimicrobial therapy.2 4 The histological features depend on the
stage of the lesion at the time of biopsy, and it is important
to note that presence of flame figures is not specific for
Wells syndrome. In the acute stage, the dermis is oedematous and infiltrated by eosinophils. At a later stage, the
eosinophils degranulate and the granules and their contents
surround dermal collagen fibres to form flame figures. As
the lesion progresses, macrophages may palisade around
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology. 17; 338347
Inclusion criteria
Inclusion criteria were intentionally broad and consisted of the
following:
1 Histological findings of moderate to severe eosinophilic dermatitis with or without collagen flame figures and an absence of
eosinophilic folliculitis and furunculosis.
2 Acute onset of severe erythema or erythroderma with or without
wheals.
3 Persistence of lesions for greater than 48 h.
4 Follow up on each case via medical records and phone calls to
local veterinarians or owners.
Drug score
A drug score was assigned for each case using a modified method
previously described.15,16 This system assigns a numerical score (+3
to 3) based on the following criteria:
1 A score of +1 (suggestive) was given if the lesions appeared
more than 7 days after first administration of the drug or less
than 1 day after re-administration.
2 A score of +1 was given if the lesions resolved after removal of
the drug with no other therapeutics. A score of 0 (inconclusive)
was assigned if other drugs were given simultaneously. A
score of 1 (incompatible) was given if the lesions persisted
despite drug withdrawal or if the patient improved without drug
withdrawal.
3 A score of 1+ was assigned if the drug was re-administered and
the patient relapsed; a score 0 if no rechallenge occurred and a
score 1 if no recurrence was seen after challenge.
4 A positive drug score was deemed suggestive of a casual drug
association. A zero score was inconclusive. A negative score
indicated that a drug association was unlikely.
Results
Twenty-nine cases met the inclusion criteria. The cases
were further subdivided into three categories. Category 1
consisted of dogs presenting for the treatment of severe
vomiting and/or diarrhoea that preceded the development of skin lesions. Category 2 consisted of dogs with
vomiting and/or diarrhoea concurrent with the onset of
skin lesions. Category 3 consisted of dogs evaluated by
a veterinarian for skin disease without gastrointestinal
signs.
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
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2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
Skin lesion
onset (days)*
Lesion type
Location
Treatment
Amoxicillin, aminopentamine
hydrogen sulphate,
metronidazole, penicillin,
reglan
Erythema, wheals
Ventrum, pinnae,
generalized
Hydroxyzine,
mesalamine, limited
antigen diet
Vomiting, diarrhoea,
haematochezia
Cholodin, metaclopromide,
metronidazole, ursodiol
Erythema, erythroderma,
wheals (dorsum), oedema
(pinnae and limbs)
Ventrum, pinnae,
generalized
Predisone
pentoxifylline
Vomiting, diarrhoea,
haematochezia,
haematemesis
Ampicillin, baytril,
cimetidine, hetastarch
Erythema, wheals,
oedema, facial swelling
Prednisone
diphenhydramine,
sucralfate,
supportive care
Mixed breed
Diarrhea, haematochezia
Amoxicillin, metronidazole,
pepcid, sucralfate
Erythematous macules,
papules
Prednisone
Shiz tzu
Vomiting, diarrhoea
Doxycycline, metaclopromide,
metronidazole, prednisone
Generalized
Prednisone
Boxer
Vomiting, haematemesis,
diarrhoea
Ampicillin, chlorpromazine,
famotidine, metaclopromide,
metronidazole
Ventrum to generalized
Cephalexin, prednisone,
betamethasone/
gentocin spray
Italian
greyhound
Vomiting, diarrhoea,
haematochezia
Ampicillin, enrofloxacin,
famotidine, metronidazole,
hetastarch, fresh frozen plasma
Erythematous macules
Diphenhydramine,
prednisone
Labrador
retriever
Vomiting, diarrhoea
Morphine, metaclopromide,
sucralfate
10
Erythematous macules
Ventrum
Diphenhydramine
Labrador
retriever
Vomiting, diarrhoea,
haematochezia
Metronidazole, metaclopromide,
hetastarch
Haemorrhagic to
erythematous plaques
Ventrum
Cefpodoxime,
metoclopromide,
prednisone
10
Basset hound
12
Vomiting, diarrhoea,
haematochezia
Ampicillin, enrofloxacin,
famotidine, metronidazole,
prednisone, sucralfate
Erythroderma, papules,
targetoid macules
Ventrum, limbs
Prednisone,
diphenhydramine,
enrofloxacin, novel
protein diet
11
Labrador
retriever
0.58
Vomiting, haematemesis,
diarrhoea
Amoxicillin, famotidine;
metronidozole
(after skin lesions)
Erythematous papules
0.015% triamcinolone
acetonide, Purina HA
Case
Breed
Jack Russell
terrier
Age
(year)
Chief complaint
Drugs administered
1.5
Vomiting, diarrhoea,
haematochezia
Doberman
Labrador
retriever
Mauldin et al.
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Table 1. Clinical features of category 1 dogs
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
Table 1. Continued
Case
Breed
Age
(year)
Chief complaint
Drugs administered
Skin lesion
onset (days)*
Lesion type
Location
Treatment
12
Mixed breed
Diarrhoea
Metronidazole
Erythematous macules
Ventrum, pinnae
Cephalexin,
diphenhydramine,
prednisone
13
Labrador
retriever
1.4
Vomiting, diarrhoea,
haematochezia
Ampicillin, erythromycin,
enrofloxacin, metronidazole
Targetoid erythematous
macules, plaques,
oedema (face)
Intensive care;
prednisone;
methylprednisolone;
Purina HA
14
Shih Tzu
Diarrhoea
Loperamide, metronidazole
Erythroderma, crusting
(head)
Diphenhydramine,
hydoxyzine
15
Golden retriever
Vomiting, haematochezia
Enrofloxacin, tagamet,
sucralfate
Erythema, oedema
Generalized
Prednisone,
diphenhydramine,
sucralfate, misoprostol
16
Akita
Vomiting, haematamesis,
haematochezia
Erythema, oedema,
crusting (pinnae/head)
Pinnae, head,
hindlimbs
Prednisone,
sucralfate, cimetidine,
misoprostol
17
Miniature
schnauzer
12
Vomiting, diarrhoea,
joint swelling
Erythema, macules,
papules
Ventrum, limbs
Intensive care;
enrofloxacin
*Time period (days) between drug administration for treatment of the gastrointestinal problem and the development of skin lesions.
In all cases, treatment consisted of withdrawal of any medication prescribed prior to the onset of skin lesions.
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Mauldin et al.
Treatment
All 17 dogs were uniformly treated by withdrawal of any
drug, or classes of drugs (e.g. beta-lactam antibiotics) that
were prescribed prior to the onset of skin lesions; however, none was treated solely with drug withdrawal. Drugs
(usually multiple) were prescribed for the gastrointestinal
signs, skin disease or both and included gastrointestinal
protectants, antibiotics, antihistamines, and glucocorticoids. Twelve dogs received prednisone (dose range: 0.8
2 mg kg1) or methylprednisolone (1.7 mg kg1). One dog
had topical concurrent betamethasone/gentamicin spray
and one dog received only topical 0.015% triamcinolone
acetonide glucocorticoid (Genesis topical spray, Virbac
AH, Inc., Fort Worth, TX, USA). Eight dogs were prescribed
antihistamines (hydroxyzine or diphenhydramine), five
dogs oral antibiotics (cephalosporins, fluoroquinolones)
and four dogs a limited antigen diet or hydrolysed protein
diet. In dog 17, the gastrointestinal signs and erythema
decreased with withdrawal of doxycycline, but the dog
remained severely lethargic. This aged dog was thought
to have multiple problems including leukocytosis of undetermined cause, positive Lyme titre, decreased albumin
and proteinuria. This dog was subsequently treated with
famotidine, metronidazole, ampicillin, gentamicin and
corticosteroids. After the biopsy results, all remaining
drugs were withdrawn and the dog was given intravenous
followed by oral enrofloxacin.
Follow up
Follow-up information was available on 16 cases. Dog 2
was euthanized a few days after the onset of skin lesions.
This dog had a history of chronic active hepatitis and a low
grade pulmonary carcinoma that was excised 8 months
prior. Of the 16 remaining cases, the average follow-up
time was 1.7 years (median: 0.9 years, range: 0.2 4.5 years).
Time to resolution was difficult to assess as many dogs
were not rechecked within the month following hospitalization. In three dogs, skin lesions resolved within 1 week
and in one dog within 4 weeks. Dog 13 was unusual in that
it had chronic pruritus and skin lesions for 6 months following the initial bout of severe vomiting and diarrhoea, then
the pruritus and skin lesions resolved completely and did
not recur during the follow-up period of 2.5 years. This dog
was maintained on Purina HA diet (Nestl Purina Petcare
Co., St. Louis, MO, USA). None of the 16 dogs had a recurrence of the skin lesions. Dog 1 had recurrent diarrhoea
and pruritus but did not develop any similar cutaneous
lesions. Dog 5 had a repeat episode of diarrhoea 5 months
later. Dog 7 had one episode of vomiting and diarrhoea
7 months following hospitalization. Six weeks after initial
presentation, dog 10 developed recurrent and severe
haemorrhagic vomiting and diarrhoea and was treated
with metronidazole with no recurrence of skin lesions.
This dog was euthanized for uncontrollable gastrointestinal
disease 2 weeks following relapse.
Category 2 Gastrointestinal disease associated with
skin lesions
Signalment
Five dogs presenting for treatment of gastrointestinal
disease also had skin lesions. This category included one
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
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Mauldin et al.
Discussion
The authors embarked on this retrospective study after
noticing acute skin eruptions in several dogs hospitalized
for treatment of gastrointestinal disease. Those cases
resembled the eosinophilic dermatitis syndrome described
by Holm et al.1 Broad inclusion criteria were purposely
maintained to determine whether this was a coincidence
or a general trend in the Veterinary Teaching Hospital referral population. The authors included in-house cases as well
as skin biopsy samples submitted to the dermapathology
service from veterinary practices in the USA. Three subpopulations of dogs were identified and the largest one
(17 of 29, category 1) had a clinical course similar to the
hospitalized patients.
The typical cases in category 1 were middle-age dogs that
were being treated for severe vomiting and/or diarrhoea
with or without haematochezia and haematemesis. After
approximately 4 days of symptomatic therapy, the gastrointestinal disease improved, but the dogs developed
diffuse erythroderma with large coalescing macules or
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2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
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Mauldin et al.
Acknowledgements
The authors would like to thank Drs James Jeffers, Jean
Greek, Robert Schick and Norma White-Withers for their
dermatological expertise and case submission, and the
referring veterinarians who graciously supplied medical
record information. The authors also thank Dr Ken Drobatz
for statistical support.
References
1. Holm KS, Morris DO, Gomez SM et al. Eosinophilic dermatitis in
nine dogs compared with eosinophilic cellulitis in humans. Journal
of the American Veterinary Medical Association 1999; 215: 649
53.
2. Wells GC, Smith NP. Eosinophilic cellulitis. British Journal of
Dermatology 1979; 100: 1019.
3. Fisher GB, Greer KE, Cooper PH. Eosinophilic cellulitis (Wells
syndrome). International Journal of Dermatology 1985; 24: 1017.
Rsum Les rapports mdicaux et les sections histopathologiques de 29 chiens prsentant une dermatite
osinophilique particulire ressemblant au syndrome de Well ont t revus dans le but dlucider la
pathognie de cette maladie. Les donnes mdicales tudies taient laspect des lsions cutanes, la
prsence de signes systmiques ou dans dautres organes, les anomalies biochimiques et les traitements.
Les sections histologiques des chiens avec une dermatite osinophilique modre svre sans folliculite
ou furonculose ont t revues pour la prsence de figures de collagne en flamme. Trois catgories de
malades ont t observes. La catgorie 1 consistait en 17 chiens traits pour vomissements et/ou diarrhe
(souvent avec hmatochzie ou hmatmse), avant (moyenne 4.6 jours) lapparition des lsions cutanes.
Quatorze chiens de ce groupe prsentaient des lsions rythmateuses (macules, papules ou plaques), qui
taient marques sur labdomen. Seize des 17 chiens ont reu de nombreux mdicaments et 59% taient
hypoalbuminmiques. La catgorie 2 consistait en cinq chiens qui prsentaient des lsions cutanes et des
symptmes digestifs initialement, et quatre de ces chiens taient hypoalbuminmiques. La catgorie 3
incluait sept chiens sans trouble digestif. Une imputabilit mdicamenteuse tait retrouve chez six chiens
du groupe 1 et chez un chien des groupes 2 et 3. Dix huit chiens prsentaient une dermatite osinophilique
sans figure en flamme, sept chiens avec des figures en flamme dbutantes, et 4 avec des figures en flamme
346
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
importantes. Ces modifications histologiques ne corrlaient pas avec la prsentation clinique. Plus de 50%
des chiens ont dvelopp une dermatite osinophilique suivant un traitement pour trouble digestif svre.
Les auteurs proposent quil sagisse dun syndrome unique qui pourrait tre associ avec une cause
mdicamenteuse.
Resumen Los historiales mdicos as como secciones histolgicas de 29 perros diagnosticados con una
peculiar dermatitis eosinoflica parecida al sndrome de Well fueron revisados en un intento de desvelar la
patognesis del sndrome. Los historiales mdicos se revisaron buscando informacin referente a la
apariencia de las lesiones dermatolgicas, la presencia o no de signos sistmicos en otros aparatos,
anormalidades en los anlisis clnicos y la historia de tratamientos farmacolgicos. Las secciones histolgicas
de perros con dermatitis eosinoflica de moderada a severa, sin foliculitis ni furunculosis se revisaron y
evaluaron para la presencia de figuras en llama en el colgeno. Se encontraron tres categorias de pacientes:
la categoria 1 correspondi a 17 perros tratados para el vmito y/o diarrea (a menudo con hematoquezia
o hematemesis) previos a la aparicin de lesiones en la piel (media 4,6 dias). Catorce de estos perros presentaron lesiones eritematosas (mculas, ppulas o placas) que fueron ms pronunciadas en el abdomen.
Dieciseis de los 17 perros recibieron variados tratamientos farmacolgicos, y un 59% fueron hipoalbuminmicos.
La categoria 2 consisti en cinco perros que manifestaron lesiones de la piel y signos gastrointestinales en
la presentacin siendo cuatro de los perros hipoalbuminmicos. La categoria nmero 3 incluy siete perros
sin enfermedad gastrointestinal. Un valor positivo para tratamiento farmacolgico se encontr en seis perros
de la categoria 1 y en un perro de cada una de las otras dos categorias. Un total de 18 casos presentaron
dermatitis eosinoflica sin figuras en llama, siete casos tuvieron figuras en llama en estados tempranos y
cuatro manifestaron figuras en llama totalmente desarrolladas. Estos cambios no se asociaron con las
categorias de presentacin clnica. Ms de un 50% de los perros desarrollaron dermatitis eosinoflica tras
el tratamiento contra una enfermedad gastrointestinal severa. Los autores proponen que este proceso
representa un sndrome unico que podra tener asociacion causal con frmacos.
Zusammenfassung Die Krankengeschichten und die histopathologischen Schnitte von 29 Hunden, die
mit einer einzigartigen eosinophilen Dermatitis diagnostiziert worden waren, welche dem Wells Syndrom
hnlich ist, wurden als Versuch, die Pathogenese dieses Syndroms zu erklren, berarbeitet. Die Krankengeschichten wurden durchgesehen, um Informationen ber das Aussehen der dermatologischen
Vernderungen, ber systemische Anzeichen in anderen Organsystemen, ber klinische Abnormalitten der
Analyten und ber die Behandlung mit Medikamenten zu erhalten. Die histologischen Schnitte von Hunden
mit moderater bis ausgeprgter eosinophiler Dermatitis ohne Follikulitis und Furunkulose wurden berarbeitet und auf das Vorhandensein von kollagenen Flammenfollikeln berprft. Die Patienten wurden in drei
Kategorien eingeteilt. Kategorie 1 bestand aus 17 Hunden, die vor dem Auftreten von Hautlsionen (durchschnittlich 4,6 Tage) auf Erbrechen und/oder Durchfall (oft mit Blut im Kot oder Bluterbrechen) behandelt
wurden. Vierzehn der Hunde aus Kategorie 1 hatten erythematse Vernderungen (Maculae, Papeln und
Plaques), welche am Abdomen besonders ausgeprgt waren. Sechzehn der 17 Hunde erhielten verschiedene
Klassen von Medikamenten, und 59% zeigten Hypoalbuminmie. Kategorie 2 bestand aus fnf Hunden mit
Hautvernderungen und gastrointestinalen Symptomen bei der Erstuntersuchung. Vier dieser Hunde
zeigten Hypoalbuminmie. Kategorie 3 bestand aus sieben Hunden ohne intestinale Erkrankung. Eine
positive Medikamentenbeurteilung wurde bei sechs Hunden der Kategorie 1 gefunden und bei je einem
Hund aus den Kategorien 2 und 3. Achtzehn Flle hatten eine eosinophile Dermatitis ohne Flammenfiguren,
sieben Flle zeigten Flammenfiguren im Frhstadium und vier zeigten gut entwickelte Flammenfiguren.
Diese Vernderungen korrelierten nicht mit den Kategorien der klinischen Prsentation. Mehr als 50% der
Hunde entwickelten eosinophile Dermatitis nach der Behandlung einer schweren gastrointestinalen
Erkrankung. Die Autoren schlagen vor, dass es sich hierbei um ein einzigartiges Syndrom handelt, welches
mit einer Reaktion auf Medikamente im Zusammenhang steht.
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
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