Unilateral laterothoracic exanthem

Unilateral laterothoracic exanthem A clinicopathologic study of forty-eight patients Catherine C. McCuaig, MD, FRCPC, a Pierre Russo, MD, FRCPC, b Julie Powell, MD, FRCPC, a Louise Pedneanlt, MD, FRCPC, c Pierre Lebel, MD, FRCPC, c and Danielle Marcoux, MD, FRCPC a Montreal, Quebec, Canada

Background: Four years ago, we began seeing young children with an unusual, predominantly unilateral, morbilliform and eczematous, self-limited cutaneous eruption. It appeared to correspond to unilateral laterothoracic exanthem (ULE) reported from France and to an eruption described as "a new papular erythema of childhood" in the United States. Objective: We conducted a prospective study of ULE to define its clinical evolution, pathology, and therapy. In addition, we performed epidemiologic and microbiologic investigations in an attempt to determine the cause of ULE. Method: We studied 48 children with ULE. In some patients, blood, urine, stool, as well as skin biopsy specimens were analyzed. Results: ULE is a morbilliform, eczematous eruption that often begins close to the axilla and spreads to become bilateral, although it usually retains a unilateral predominance. Patients' mean age at onset is 24.3 months, with a female predominance (2:1) and mean duration of 5 weeks, followed by spontaneous resolution that may or may not be improved with topical corticosteroids. It is characterized by a unique eccrine lymphocytic infiltration. Although signs of infection were reported by most patients, no one infectious agent was identified. No significant epidemiologic factor was found. Conclusion: ULE, in young children, is a self-limited morbilliform and scarlatiniform eruption that may represent a specific skin reaction to one or more infectious agents. (J Am Acad Dermatol 1996;34:979-84.)

The term unilateral Iaterothoracic exanthem (ULE) in children was coined by Bodemer and de Prostl, 2 in 1992 to describe a distinct clinical entity. They described 18 children (mean age, 23.3 months) who had a characteristic skin eruption that began unilaterally, close to the axilla, with centrifugal spreading, and lasted 4 to 6 weeks with spontaneous resolution. In 1993, these authors expanded their series to include 30 cases of ULE. 3 In 1994, Taieb et al. 4 described 21 children in southwest France with ULE, which they proposed be named "asymmetric periflexural exanthem of childhood" (APEC). The latest case reports include two Italian infants with

ULE, 5 an American girl, 6 and 187 patients in Hungary. 7 Brunner, Rubin, and Dunlop s described similar patients in 1962 in an article entitled " A New Papular Erythema of Childhood" in which 75 children in Chicago were described. Melski 9 also reported this eruption in the midwesteru United States. Laur 1° summarized 275 cases seen in Texas during the past 40 years and suggested the term lichen miliaris. The purpose of our study was to determine the clinical evolution of ULE, its response to therapy, and its histopathologic features. Possible epidemiologic factors and microhiologic agents were studied. METHOD

From the Dermatology Service, Department of Pediatrics, a the Department of Pathology, b and the Department of Microbiology and Infectious Diseasesf H6pital Sainte-Justine. Accepted for publication Dec. 5, 1995. Reprint requests: Catherine C. McCuaig, MD, Dermatology Service, Department of Pediatrics (7-9), Htpital Sainte-Justine, 3175, C6te Ste-Catherine, Montreal, Quebec, Canada, H3T 1C5. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0 16/1/70982

Forty-eight consecutive cases of unilateral laterothoracic exanthem were studied between November 1992 to July 1993 and January 1994 to March 1994. We gathered these cases by sending out letters to regional pediatricians describing this condition and asking them to refer similar cases for evaluation. Patients were enrolled on the basis of the characteristic predominantly unilateral morbilliform and eczematous eruption. Our protocol was ap979

980 McCuaig et al.

Fig. 1. Bilateral, but primarily right-sided, morbilliform eruption with involvement of the axilla, lateral trunk, and abdomen (ULE).

proved by the hospital ethics committee and parental consent was obtained when more extensive investigation was performed. After a detailed history and physical examination, clinical photographs were obtained in 30 of 48 patients. Complete blood cell count with differential was assessed in 26 patients, erythrocyte sedimentation rate in 23, Creactive protein (CRP) in 14, antistreptolysin O (ASO) in 12, and rapid plasma reagin in 4. Serum specimens were obtained in 16 of the 48 patients on two separate occasions, 2 weeks apart and at least 1 week into the illness. Specific IgM antibodies directed against a variety of viruses were detected by enzyme immunoassay (Behringwerke, Marburg, Germany for cytomegalovims, herpes simplex virus, variceila-zoster vires, measles and rubella viruses and Ortho Pharmaceuticals for Epstein-Barr virus [EBV] IgM) according to the manufacturer' s instructions. Serology for the detection of parvovims B-19-specific IgM antibodies was performed by radioimmunoassay. IgG titers to human herpesvims 6 (HHV-6) were measured on paired sera by indirect immunofluorescence. The IgG response to the viral capsid antigen of EBV was measured by standard indirect immunofluorescence on productive cell lines such as B95-8 fixed in acetone, 11 whereas IgG antibody titers to the nuclear antigens of EBV were measured by anticomplement immunofluorescence12 on Raji cells fixed in acetone/methanol (1:1). Complement fixation was used to demonstrate seroconversion or a fourfold increase in antibody titer against Mycoplasma pneumoniae on a pair of sera from most patients being exanained. 13 Borrelia

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serology was obtained in 12 patients. Four patients had hepatitis B serology pertbrmed with the microparticlebased enzyme immunoassay (Abbott Laboratories, Abbott Park, Ill.). Each of 15 skin biopsy specimens (3 ram) was fixed in formalin-Bouin's and processed routinely. Paraffinembedded sections were also stained for UCHL1 (T-cell marker, DAKO-CD45RO) and L-26 (B-cell marker DAKO) with an avidin-biotin peroxidase technique. Seven additional skin biopsy specimens were obtained. These were snap frozen and sections stained for IgG, IgA, IgM, Clq, C3, and fibrinogen by immunofluorescence and for T-cell CD4 and CD8 markers (Leu-2a and Leu3a, Becton Dickinson, Mountain View, Calif.) by immunoperoxidase. In two of the seven specimens the tissue was also fixed in 3% glutaraldehyde and processed for transmission electron microscopy. Twenty-one throat specimens were cultivated for [3-hemolytic streptococci. Twelve stool specimens were cultured for enteric pathogens. 14 Nine skin biopsy specimens were cultured for aerobic and anaerobic bacteria. Direct examination of the specimens was done with the use of Gram and Ziehl-Nielsen stains as well as potassium hydroxide. Cultures were also done for fungi, mycobacteria, Mycoplasma hominis, and Ureaplasma urealyticure. TM Urine bacterial cultures were performed in 11 patients. Skin biopsy (n = 9), throa((n = 15) and stool (n = 11) specimens were processed according to standard methods for viral culture. TM A definitive viral identification was made by indirect immunofluorescence assay. Topical corticosteroids were administered to 25 patients (52.1%). Hydrating creams were used by the majority of patients. Systemic antihistamines were given for severe pruritus.

RESULTS History and physical examination The 48 patients consisted of 30 girls and 18 boys (female/male ratio, 2:1). The mean patient age was 24.3 months (standard deviation, 9.7 months; range, 12 to 63 months). The mean duration of the eruption was 5 weeks (standard deviation, 1.96 weeks). The shortest eruption lasted 1.5 weeks and the longest 12 weeks. The majority of children were white, although one child was black and another Asian. All lived within a 100-mile radius of Montreal, Quebec. Most patients were seen in winter and spring (85.4%), with the rest seen in the autumn; the study period did not include the summer. In the majority of patients, the onset of the skin eruption was unilateral, close to the axilla, and less often the inguinal area (Fig. 1). Spread was centrif-

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McCuaig et al. 981

Fig. 3. Perieccfine and intraeccrine duct inflammation found in deeper dermis. (Hematoxylin-phloxin-saffran; original magnification x500.)

Fig. 2. ULE. Reticulated plaques on the left posterior thigh. ugal with new patches appearing on the opposite side of the body and at distal sites often separated by normal skin (Table I). At the time of consultation 53.4% of cases were bilateral, although one side was usually more involved. No statistically significant difference was found in the frequency of right- or left-sidedness (55.3% and 44.7%, respectively). The eruption consisted of discrete 1 m m erythematous papules, often surrounded by a pale halo, as well as coalescent poorly delimited eczematous plaques, often in the same patient. Although early the exanthem was primarily morbilliform, with time eczematization increased. Older plaques developed central dusky gray discoloration. The plaques were at times reticular and occasionally annular (Fig. 2). More rarely, they were bright red and edematous. Vesicles were seen in only one patient and purpura on only one occasion. Excoriations were occasionally present. No lichenification was noted. Pruritus was reported by 30 patients (62.5%) and was usually mild (80%). Later, furfuraceous desquamation was seen in all patients. Although many patients reported brief mild recurrences 1 to 4 weeks after spontaneous clearance, no long-term recurrences have been reported. Mild regional lymphadenopathy was noted in eight patients (16.7%). There was no enanthema or hepatosplenomegaly. The ears, nose, and throat were normal.

Fig. 4. Exocytosis and spongiosis found primarily arotmd terminal intraepidermal portion of eccfine duct. (Hematoxylin-phloxin-saffran stain; original magnification x120.) The response to topical corticosteroids was variable. Subjective improvement was noted in 11 patients (44%), although no change was seen in another 11 (44%) and worsening was observed in three (12%). Hydrating creams and antipruritic bath oils alleviated the eruption, particularly in the late desquamative phase. Antihistamines were beneficial when significant pruritus was present. Malaise was generally absent, although 36 patients (77.1%) had signs of infection before (78.4%) or during (21.6%) the exanthem; these included fever, upper respiratory tract infection, vomiting, and diarrhea (see Table ID. Nine patients (18.8%) had received an antibiotic before the skin eruption. Two patients reported diarrhea before the exanthem. Campylobacterjejuni was isolated from their stool. One patient had roseola 3 weeks before the eruption. Only six children (12.5%) had been vaccinated within a month of the onset of the exanthem.

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Table I. Unilateral laterothoracic exanthem sites Site

Axilla Trunk Arm Thigh Forearm Leg Face Scalp Hand Foot Genitals Buttocks

No. of patients (N = 48)

46 46 43 35 26 13 7 0 6 3 4 2

Table II. Accompanying signs of infection in unilateral laterothoracic exanthem

%

95.9 95.9 89.6 73.0 54.2 27.1 14.6 0 12.6 6.3 8.3 4.2

No significant associated environmental factor was found. No insect bites or travel outside the province was reported. One patient subsequently reported a previ spider bite on the side on which the exanthem initially developed. Family history including recent infections and skin eruptions was noncontributory except in two patients. In one, the father had had a unilateral periaxillary eruption 2 weeks before his child' s eruption. In another, the father had had an eczematous patch limited to the right forearm at the same time his child had bilateral ULE with right predominance. L a b o r a t o r y investigations

Laboratory investigations revealed a normal leukocyte count in all 26 patients tested. Relative lymphocytosis was observed in 37%, but no atypical lymphocytes were seen. C-reactive protein was normal in 14 cases. An increased erythrocyte sedimentation rate was observed in only 1 of 23 patients in whom the C-reactive protein was normal. This patient had been hospitalized for severe diarrhea resulting from C. jejuni infection, and his exanthem lasted the longest (12 weeks). Antistreptolysin O was negative in all 11 patients, and rapid plasma reagin was absent in four. Throat cultures were negative for all patients but one. Parainfluenza virus type I was isolated from the throat of a child who had an upper respiratory tract infection before the onset of his eruption. Bacterial and viral cultures of the stool as well as urine bacterial cultures were negative. No vires-specific IgM antibodies were detected on the sera evaluated. The human herpesvirus type 6, EBV, and M. pneumoniae serologies were negative; all patients tested re-

No. of patients

Signs

(N = 48)

%

None Present (->1 sign) Upper respiratory infection + (otitis) Fever Other* Diarrhea

11 37 18 24 5 15

22.9 77.1 48.6 64.9 13.5 40.5

*Vomiting,rash with fever, urinary tract infection.

mained seronegative or demonstrated stable titers of antibodies when paired sera were evaluated in parallel. One child had antibodies against hepatitis B surface antigen, although the antigen itself was absent. All skin biopsy specimen cultures were negative for bacteria, viruses, fungi, and Mycoplasma. Histopathologic findings

In all 15 patients, examination revealed a mild to moderate, perivascular, predominantly lymphocytic infiltrate; in most, the infiltrate also clustered around and infiltrated the dermal eccrine ducts, although the secretory coils were largely intact (Fig. 3). In the epidermis, mild exocytosis and spongiosis were noted in most, mainly around the intraepidermal terminal portion of the eccrine ducts (Fig. 4). There was no associated hyperparakeratosis or parakeratosis. Apocrine glands were not present in any specimens. The infiltrate was composed primarily of T lymphocytes; staining for T helper/suppressor markers revealed a predominance of CD4 + T cells. Immuno fluorescence staining did not reveal significant immune deposits in the epidermal basement membrane, dermal vessels, or eccrine structures. The results of electron microscopy performed in two specimens were characterized principally by lymphocytic infiltration of eccrine ducts with degenerative changes in the epithelial cells. DISCUSSION

ULE is usually characterized by its asymmetric localization and unilateral onset. It begins close to the axilla, lateral mink, upper inner arm, or groin. The exanthem then extends centrifugally to become bilateral in almost all patients. At times, only the history of the unilateral onset will aid in the diagnosis. Thus the "unilateral" in ULE can be misleading. Although the eruption is primarily on the trunk and

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proximal extremities, contrary to previous reports, we did find patients with involvement of the face, genitals, and dorsal aspects of the hands and feet as well as palmoplantar surfaces (see Table I). Although most of our patients were white, we report the first cases of ULE in a black child and in an Asian infant. We also found the individual lesions are micropapules surrounded by a halo, suggestive of a viral eruption, and with time eczemafization, coalescence, and the formation of dusky centers, and, finally, desquamation. Overlap of these phases occurs. Reticulated and annular patches, excoriations, vesicles, and purpura may be seen. Lichenification is generally not a feature. Pruritus was present in most children (62.5%), which, although usually mild, is occasionally severe enough to require systemic antihistamines. Treatment is directed to alleviation of symptoms. Spontaneous resolution is the rule. 1-4 No clear epidemiologic factor was made evident. A viral cause was suggested by the clinical appearance of the eruption as well as the clinical evolution; signs of infection were present in 77% of children, the majority occurring before the eruption (Table II). However, there was no statistically significant association between the signs of infection and the season. The fact that older children and adults are not generally affected by ULE as well as the lack of recurrence in the same patient suggests that immunity may develop. Possible contagion was also suggested by the family history in two of our patients as well as reports by others. 2 The microbiologic evaluation, however, was unrewarding. Although the possibility of inoculation disease with Spiroplasma has been raised,4, 16 Mycoplasma cultures were negative and serologic testing for Lyme disease was negative. Clinical differential diagnosis of ULE includes a nonspecific drug or viral eruption, scabies, scarlet fever, contact dermatitis, tinea corporis, miliaria, Gianotti-Crosti syndrome, and atypical pityriasis rosea. Most of our patients had been suspected to have contact dermatitis or, less commonly, tinea corporis. It is interesting to compare ULE with pityriasis rosea, as did Melski 9 and Laur, 1° and with the Gianotti-Crosti syndrome.17, 18 In ULE and pityriasis and rosea, the eruption is localized on the trunk and the proximal extremities and is acral in Gianotti-Crosfi syndrome. ULE presents with small papules with a unilateral predominance, whereas pityriasis rosea has oval scaly plaques in a bilateral "Christmas-

McCuaig et al. 983 tree" distribution 17 and Gianotti-Crosti syndrome demonstrates a papulovesicular bilateral acrolocated eruption. 19 All three eruptions share the features of a variable time course and spontaneous resolution. Pruritus (occasionally severe2) and possible viral origin are common to all three. The distinctive clinical and histologic features are probably patterns related to the infectious agent incriminated, to patients' characteristics such as age and immune status (or both) or the quantity of the infectious inoculum. Bodemer and de Prost 1 described the histologic features in two patients with ULE. One showed a nonspecific superficial dermatitis (the lesions had been present for 15 days). The other revealed a perivascular and periappendageal lymphocytic infiltrate with epidermal spongiosis and mononuclear cell exocytosis. Laur 1° described a lichenoid infiltrate that was superficial and at times deep with occasional extravasated erythrocytes. The latter histologic findings were not observed in our patients. We do agree with the aforementioned authors that the histologic pattern seen may vary depending on the time at which the skin biopsy specimen is taken. 1, l0 The unusual histologic feature in our patients was the prominent lymphocytic infiltration of eccrine glands and ducts, including their terminal intraepidermal portion. Inflammation of the eccrine unit is a feature of miliaria and occurs as a result of cytotoxic drugs. 20 In miliaria, the inflammatory changes are essentially confined to the intraepidermal portion of the eccrine ducts and are usually associated with a subcorneal vesicle, whereas cases of drag-induced eruptions demonstrate a primarily neutrophilic infiltrate. 2° None of our cases was associated with use of a cytotoxic drag. ADDENDUM:Since submission of this manuscript, we have examined 29 additional cases of ULE, bringing the total to 77. W e are grateful to Westwood-Squibb Canada, who kindly provided the financial contribution necessary for pubfication of the color photographs. REFERENCES

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