Non–Sexually Related Acute Genital Ulcers in 13 Pubertal Girls a Clinical and Microbiological Study

STUDY Non–Sexually Related Acute Genital Ulcers in 13 Pubertal Girls A Clinical and Microbiological Study

David Farhi, MD; Jeanne Wendling, MD; Emmanuel Molinari, MD; Jacqueline Raynal, MD; Guislaine Carcelain, MD; Patrice Morand, MD; Marie-Franc¸oise Avril, MD; Camille Francès, MD; Flore Rozenberg, MD; Monique Pelisse, MD; Nicolas Dupin, MD, PhD

Objective: To describe the clinical and microbiologi- Results: Mean age was 16.6 years (range, 11-19 years). cal features of acute genital ulcers (AGU), which have Eleven patients denied previous sexual contact. A fever or been reported in virgin adolescents, predominantly in girls. flulike symptoms preceded AGU in 10 of the 13 patients (77%), with a mean delay of 3.8 days before the AGU on- Design: Descriptive study. We collected data on the clini- set (range, 0-10 days). The genital ulcers were bilateral in cal features, sexual history, blood cell count, biochem- 10 patients. The final diagnosis was Epstein-Barr virus pri- istry, microbiological workup, and 1-year follow-up. mary infection in 4 patients (31%) and Behc¸et disease in 1 patient (8%). No other infectious agents were detected in this series. Setting: Departments of dermatology of 3 university hospitals in Paris. Conclusions: We recommend serologic testing for Ep- stein-Barr virus with IgM antibodies to viral capsid an- Patients: Thirteen immunocompetent female patients tigens in non–sexually related AGU in immunocompe- with a first flare of non–sexually transmitted AGU. tent patients. Further microbiological studies are required to identify other causative agents. Main Outcome Measures: Clinical and microbiological data, using a standardized form. Arch Dermatol. 2009;145(1):38-45

HE MOST COMMON CAUSES OF ably underrecognized by clinicians. acute genital ulcers (AGU) Moreover, when considering the litera- are herpes simplex virus ture on this issue since the seminal study (HSV) and aphthosis. Since by Lipschütz,1 we suspected that in fact the beginning of the 20th several distinct nosological entities may century,T several cases of virgin patients with have been reported under the entry Lip- AGU that were not consistent with HSV in- schütz’s ulcer, thus further hampering the fection or aphthosis were reported. In 1913, understanding of this syndrome. We there- Lipschütz1 proposed a classification of non- fore suggest avoiding this appellation, and venereal AGU in 3 categories. Two catego- propose herein major and minor criteria ries fall in the pattern of aphthosis, being to designate a peculiar clinical situation idiopathic or secondary to Behc¸et disease that requires prompt diagnosis and man- or Crohn disease. The third type of AGU agement, often in an emergency context: was described as sudden, gangrenous, self- the first flare of AGU in an immunocom- limiting, with nonrelapsing ulcers, occur- petent patient without any context of sexu- ring mainly in non–sexually active girls and ally transmitted disease (STD) or aphtho- young women and associated with sys- sis. Our aim was to describe the clinical temic signs evocative of infection. During and microbiological features of the first the 20th century, nonherpetic AGU has flare of AGU in a series of these patients. been associated with several infectious dis- eases, including salmonellosis1-3 and infec- METHODS tious mononucleosis.4 However, the etiological diagnosis of STUDY DESIGN AND PATIENTS AGU remains a difficult one, partly be- Author Affiliations are listed at cause of the large array of potential pre- We designed a descriptive study of 13 con- the end of this article. cipitating factors,5 many of which are prob- secutive immunocompetent patients with a first

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 flare of non–sexually related AGU. Patients referred to the de- sisted until day 37. At day 65, she presented with several partments of dermatology of 3 university hospitals in Paris from painful aphthoid ulcerations of the tongue that healed January 1, 1996, through December 31, 2006, were prospec- within 15 days. tively included if they presented with 5 major and 1 of 2 mi- Serologic test results for CMV, human immunodefi- nor criteria. Major criteria included (1) presenting with a first ciency viruses 1 and 2, parvovirus B19, hepatitis B and flare of AGU; (2) being younger than 20 years; (3) absence of sexual contact during the past 3 months; (4) absence of im- C viruses, syphilis (Treponema pallidum hemagglutina- munodeficiency; and (5) acute course of the genital ulcer (ie, tion [TPHA] and VDRL tests), toxoplasmosis, and p24 abrupt beginning and healing without scarring within 6 weeks). antigenemia were negative at different sampling times. Minor criteria were related to the symptomatology of the geni- At day 7 of the ulcers, findings were positive for IgM tal lesions, which may present in the following 2 possible pat- antibodies to the EBV capsid antigen (VCA) and nega- terns: (1) 1 or several deep, well-delimited, painful ulcers, with tive for IgG antibodies. At day 15, findings for IgM and a necrotic and/or fibrinous center or (2) a bilateral “kissing pat- IgG anti-VCA antibodies were strongly positive, whereas tern” (a mirrorlike vulvar distribution). those for anti-EBV nuclear antigen (EBNA) were nega- The exclusion criteria were (1) a history of genital aphtho- tive, confirming primary infection with EBV. Other bio- sis or STD; (2) clinical or microbiological evidence of genital logical variables are summarized in Table 1. herpes or another STD; and (3) immunodeficiency. Given its high incidence in the general population, a history of oral aph- The Tzanck test showed no cytopathogenic effect. thosis was not an exclusion criterion. Because this was a de- Histopathological examination of a mucosal biopsy scriptive, noninterventional study, the project did not require specimen showed a necrotic epithelium and a polymor- approval by an institutional review board. phic dermal infiltrate that consisted of neutrophils and mononuclear cells expressing preferentially the CD8 DATA COLLECTION antigen (Figure, B). Results of in situ hybridization revealed EBV transcripts (EBV-encoded small RNA We collected the following data: age, sex, sexual history, com- [EBER] and BamHI H left frame 1 [BHLF-1 RNA]) plete clinical examination, symptomatology of the genital ul- (Figure, C), whereas immunohistochemistry revealed cers, time to healing of the genital lesions, blood cell count, EBNA-2 and BamHI Z EBV replication activator biochemistry (measurement of liver enzyme levels and kidney (ZEBRA) proteins (Figure, D). Quantification of EBV function), and results of a search for infectious agents includ- was performed at sequential intervals in the serum ing human immunodeficiency virus, cytomegalovirus (CMV), samples and in the vulvar lesion. Epstein-Barr virus (EBV), syphilis, and toxoplasmosis. The pres- At day 6, the serum load of EBV was in the range of ence of HSV was investigated by means of repeated serologic examinations and/or local swabbing (for culture and/or poly- the serum loads commonly found in patients with EBV merase chain reaction). In some cases, other laboratory work- primary infection (373 copies/mL), whereas the EBV load ups were implemented, including genital mucosal biopsy for was higher in the mucosal swab (1737 copies/mL). The histopathological examination (in 5 patients). serum EBV load remained high at day 15 (336 copies/ One year after the flare of AGU, a standardized form was mL) and decreased to less than 3 copies/mL at day 24, sent to the patients to assess occurrence of relapses of AGU or without any subsequent flare of serum EBV load during other medical problems. the 4-month virological follow-up. The CD8 cells specific for EBV were quantified at dif- LITERATURE REVIEW ferent times, using an interferon ␥ enzyme-linked im- munospot assay (IFN-ELISPOT kit; Diaclone Research, We conducted an extensive and systematic MEDLINE search Besanc¸on, France). At day 21, a weak response against using the key words acute and genital or vulvar and ulcers or ul- latent (EBNA-3A, EBNA-3C, and latent membrane pro- cus vulvae acutum or Lipschütz. We further searched all refer- tein 2 [LMP-2]) and lytic (EBV immediate-early gene ences in the retrieved articles. Thus, we collected a total of 32 product BMLF-1) antigens was detected. At day 65, the relevant articles on the topic. response against BMLF-1 displayed a 10-fold increase (257 spot-forming cells per 106 peripheral blood mono- REPORT OF A CASE nuclear cells). At 6 months, the BMLF-1 response van- ished and was replaced by a strong response against the In March 2000, a previously healthy 19-year-old woman LMP antigen (217 spot-forming cells per 106 peripheral presented with painful AGU, odynophagia for 10 days, blood mononuclear cells). and intense fatigue for 2 days. She denied previous Six months later, the patient remained free of symp- sexual contact at repeated interviews. On physical toms, findings for anti-EBNA antibodies were positive at examination, her temperature was 40°C and she had high titers, and blood lymphocyte levels were within the pharyngeal edema, lymphadenopathies, and vulvar reference range. One year later, she had not experi- ulcers (Figure,A,andTable 1). Her hymen was enced a relapse. intact. At day 10, she developed a grayish white membranous tonsillitis, with enlarged and swollen cervical lymph nodes. Pharyngeal culture results were negative RESULTS for group A streptococci. Cefpodoxime proxetil therapy was then started with substitution of josamycin at day From 1996 to 2006, 13 patients (including the case de- 13. At day 25, she developed a rash of the 4 extremities, scribed in the preceding section) were included in a clini- consisting of scattered erythematous small papules that cal and virological study (Table 1). Unless otherwise in- resolved spontaneously within a few days. Fatigue per- dicated, data are expressed as mean (SD).

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C D

Figure. Clinical and virological findings in patient 1. A, Acute necrotizing genital ulcerations of the labia minora, with a kissing pattern. B, Immunostaining with anti-CD8 antibodies shows infiltrating lymphocytes expressing CD8 (red) (original magnification ϫ20). C, In situ hybridization with an Epstein-Barr virus (EBV)–encoded small RNA probe shows 2 cells with positive reactions (arrows) (original magnification ϫ40). D, Immunostaining with anti–BamHI Z EBV replication activator antibodies shows 1 cell with a positive reaction (nuclear, red) (original magnification ϫ100).

DEMOGRAPHIC DATA The genital ulcers were bilateral in 10 of 13 patients (77%), with a peculiar kissing pattern in 9 of 10 (90%). All of the patients were female. Mean age was 16.6 Nine of 13 patients had a medical history of transient oral (2.8) years (median age, 18 years; range, 11-19 years). erosions, diagnosed as aphthae. Eleven of 12 patients (92%) denied previous sexual The AGU was associated with an EBV primary infec- contact. Patient 12 had had previous sexual inter- tion in 4 of 13 patients (31%). Biological mononucleo- course, although not during the 3 months before the sis syndrome (hyperbasophilic atypical lymphocytes) was AGU. present in 3 of the 4 patients with EBV primary infection (75%) vs 1 of the 7 patients without EBV primary CLINICAL PRESENTATION infection (14%) (P=.09). No other infectious agents were AND MICROBIOLOGICAL DATA detected in any of the 13 patients; all patients who un- derwent testing had negative serologic findings for HIV Seven of the 13 patients (54%) had prodromic tonsilli- (12 patients) and syphilis (6). All patients who under- tis, which occurred with a mean delay of 8.6 (6.0) days went testing had repeated negative test results or a for- before the AGU onset (median delay, 7 days; range, 3-18 merly acquired immunity profile for HSV (10 patients), days). A fever or flulike symptoms preceded AGU in CMV (12), and toxoplasmosis (6) antibodies. The kiss- 10 of 13 patients (77%), with a mean delay of 3.8 (3.1) ing pattern of the ulcerations was present in all 4 of the days before the AGU onset (median delay, 3 days; range, patients with EBV primary infection (100%) vs 5 of the 0-10 days). 9 patients without EBV primary infection (56%).

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Patient Features Lymph HSV Serum EBV Genital EBV Duration No. of Genital Node Systemic Blood Cell Workup Workup Workup of AGU, Final (Age, y) Ulcers Findings Signs Count Findings Findings Findings Treatment d Diagnosis 1 Deep ϩ Flulike Lymphopenia Serologic: − Seroconversion ϩ Valacyclovir 17 EBV PI (19) kissing-pattern, (Bilateral, symptoms (lymphocyte of EBNA (ISH, IHC) hydrochloride, 5- to 20-mm cervical (fever and count, antibodies in cefpodoxime necrotizing ulcers and fatigue); 1250/µL); Յ6 mo; PCR proxetil, on labia minora, inguinal) purpuric inversion of for EBV on josamycin with well-defined micropapular the CD4:CD8 serum, ϩ edge; moderate acral rash; ratio; AL, 7%; edema oral erosions; anemia cytolytic hepatitis 2 Necrotic 1-cm − None Within Serologic: IgGϩ, EBNA: IgGϩ, − Cefpodoxime 28 Idiopathic AGU (19) kissing-pattern reference IgM− IgM− (IHC) ulcers on labia range minora 3 Multiple, ϩ Flulike Lymphopenia; Serologic: − Seroconversion − Valacyclovir 15 EBV PI (19) geographic, 2-cm, (Bilateral, symptoms no AL of EBNA (Culture, soft and tender inguinal, (fatigue, antibodies in IHC) kissing-pattern tender) fever, and Յ20 d ulcers on labia headache); minora oral erosions 4 Multiple − Flulike Within Serologic: − VCA: −; PCR − Valacyclovir 15 Behc¸et disease (19) kissing-pattern symptoms reference for EBV on (Culture) (6 mo after AGU: ulcers on labia (fever); range serum: − relapsing bipolar minora; edema cytolytic aphthosis, hepatitis pseudofolliculitis, arthritis) 5 Ulcer on right ϩ Flulike Lymphocyte NA EBNA NA None 9 Idiopathic AGU (16) labium minus (Bilateral symptoms count, antibodies: − inguinal) (fatigue and 4200/µL; (twice in fever) AL, 3% Յ36 d) 6 Asymmetric necrotic − Flulike Within Serologic: − VCA and − Amoxicillin 35 Idiopathic AGU (12) ulcers on labia symptoms reference EBNA: − (Culture) minora; edema (fever); range (twice in cytolytic Յ37 d) hepatitis 7 Symmetric − Flulike Leukocytosis Serologic: Seroconversion − None 15 EBV PI (15) kissing-pattern symptoms (lymphocyte consistent with of VCA (Culture, ulcers on labia (fever); count, ancient antibodies PCR) minora cytolytic and 10 100/µL); acquired in Յ14 d cholestatic AL, 18%; immunity; hepatitis thrombopenia culture and PCR (platelet count, negative on 129 000/µL) genital swabs 8 Kissing-pattern − Flulike NA Serologic: HSV1 VCA: IgGϩ, NA Valacyclovir 15 Idiopathic AGU (17) ulcers on labia symptoms and HSV2 tests: IgM−; minora IgM−, IgG− EBNA: − 9 Necrotic symmetric − Flulike Leukocytosis Serologic: HSV1 MNT: ϩ NA None 15 EBV PI (18) kissing-pattern symptoms (WBC count, and HSV2 tests: ulcers on labia (fever and 12 800/µL); IgM−, IgG−; minora and myalgias); AL, Ͼ50% culture: − majora cytolytic hepatitis 10 Large necrotic − Flulike Within NA VCA: IgGϩ, − None 15 Idiopathic AGU (14) kissing-pattern symptoms, reference IgM− (Culture) ulcers on labia abdominal range minora; edema pain, and diarrhea; cytolytic hepatitis 11 Small necrotic ulcer − Abdominal Within NA NA − Amoxicillin 8 Idiopathic AGU (18) on right labium pain reference (IHC) minus range 12 Necrotic bilateral ϩ Flulike Within Serologic: MNT: −; VCA: NA None 21 Idiopathic AGU (19) kissing-pattern (Cervical symptoms reference consistent with IgGϩ, IgM− ulcers on labia and (fever) range ancient minora with inguinal) acquired marked edema immunity; culture: − 13 Painful ulcer of the ϩ None NA Serologic: −; VCA: −; EBNA: − NA Valacyclovir 15 Idiopathic AGU (11) right labium culture: − minus

Abbreviations: AGU, acute genital ulcers; AL, atypical lymphocytes; CMV, cytomegalovirus; EBNA, Epstein-Barr virus (EBV) nuclear antigen; HSV, herpes simplex virus; IHC, immunohistochemistry; ISH, in situ hybridization; MN, mononucleosis; MNT, monospot test (heterophile antibody); NA, not assessed (or not reported); PCR, polymerase chain reaction; PI, primary infection; VCA, viral capsid antigen; WBC, white blood cell; ϩ, positive; −, negative. SI conversion factors: To convert lymphocytes and WBCs to ϫ109/L, multiply by 0.001; platelets to ϫ109/L, multiply by 0.001.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 A medical history of oral erosions diagnosed as aph- by 21 days. Huppert et al15 considered that most of these thae was present in 1 of the 4 patients with EBV primary cases of AGU were possibly genuine genital aphthae. How- infection (25%) vs all 8 of those without EBV primary ever, the inclusion criterion in their series was AGU with infection (100%) (P=.02). negative HSV test results and, therefore, that these cases Cytolytic hepatitis was present in 3 of the 4 patients might be different from those in our series, which may with EBV primary infection (75%) vs 3 of the 7 without explain the lower rate of EBV-related AGU reported in EBV primary infection (43%). the series by Huppert et al.15 For example, 3 of their pa- Results of the histopathological examination were not tients had a history of AGU,15 whereas this feature was helpful for the diagnosis in any of the 5 patients who un- an exclusion criterion in our series. derwent mucosal biopsy and usually showed a nonspe- In the highlighted case from our series of patients, we cific lymphocytic inflammatory dermal infiltrate. demonstrated the presence of EBV in mononuclear cells infiltrating the vulva. We showed the expression of both FOLLOW-UP RNA (EBER and BHLF-1) and proteins (EBNA-2 and ZEBRA), suggesting that EBV may replicate in the mu- Six patients were treated with valacyclovir hydrochloride cosa, or at least that a part of the lytic cycle could occur. (46%) and 4 with a ␤-lactamine (31%). The mean delay However, the proportion of EBV-positive cells was low, before healing was 16.8 (7.4) days (median delay, 15 days; suggesting that the ulceration results more from an im- range, 8-35 days), without a significant difference accord- mune reaction associated with EBV than from a direct ing to the final diagnosis (EBV primary infection vs other cytopathogenic effect of the virus itself. Moreover, in our 15 AGU). series, as in others, most of the pubertal non–sexually Three patients (23%) experienced 1 relapse of AGU dur- active patients with AGU had no evidence of associated ing the following year. None of them was diagnosed as hav- acute systemic infection. Therefore, it might be hypoth- ing EBV primary infection during the first flare of AGU. esized that AGU in these patients result from a reac- One of them was later diagnosed as having Behc¸et disease. tional nonspecific inflammatory process. This may explain why AGU have been described with a large spectrum of acute infection, such as CMV, influenza, salmonella, COMMENT and toxoplasmosis.2,3,7,8,25,26 In addition, some authors have suggested that these The first flare of a nonherpetic AGU in an immunocom- peculiar forms of AGU in non–sexually active adoles- petent patient without an STD is a difficult etiological cents are a clinical form of primary genital aphthosis.15 problem that is often diagnosed in excess as genital her- In 24 previously published cases of EBV primary in- pes or aphthosis or even sexual abuse in young patients. fection associated with AGU,5,9,11,13,14,16,18-24 mean age was We presented herein a series of 13 consecutive cases of 15.1 years, which is similar to our findings, and 23 of 24 AGU in female patients younger than 20 years, and we patients (96%) were female. In our series, 92% of the pa- showed that one-third of these AGUs were associated with tients denied previous sexual contact; in the literature, 17 EBV primary infection. of 24 patients (71%) had never had sexual contact; 4 (17%) Unlike herpes and aphthosis, AGUs related to EBV pri- had had sexual intercourse4,5,17; and 3 (13%) had had only mary infection are typically associated with the absence orogenital (2 patients)10,18 or digital-genital (1)23 contact. of further relapse of genital ulcers. This clinical syn- On clinical examination, 8 of 22 previously published cases drome should lead to an oriented microbiological workup of AGU (36%) had a kissing pattern of ulcers, 13 (59%) in search of previously reported causative infectious had sore throat, 16 (73%) had lymphadenopathy, and all agents, including EBV, CMV, salmonella, and toxoplas- had systemic signs, the most common being fever (20 of mosis.2-8 Our study confirms that the most frequently re- 22 [91%]) and fatigue (14 of 22 [64%]). In our study, the ported infectious agent associated with a first flare of non- mean duration of genital lesions was 17 days, which is com- herpetic AGU is EBV. parable to the duration of 19 days reported in the litera- We retrieved 18 articles that reported 24 cases of a first ture. This healing delay is comparable to that of 12 to 16 flare of AGU associated with EBV primary infection,4,5,9-24 days reported for genital herpes primary infection.27-29 In including 15 cases in girls without previous sexual con- 9 of the 21 reported cases (43%), acyclovir was intro- tact (Table 2). All cases were confirmed by serologic test duced before the correct diagnosis of EBV primary infec- results consistent with EBV primary infection. In 4 cases, tion was made (5 of 13 [38%] in our series); this reflects local workup identified EBV on the genital lesions.4,21,23 that genital herpes is the most commonly suspected dif- In 2006, Huppert et al15 reported a series of 20 cases ferential diagnosis. Indeed, genital herpes should always of presumed non–sexually transmitted AGU in female pa- be ruled out first in a patient with AGU. However, the clini- tients aged 10 to 19 years. Systemic signs such as fever, cal presentation of genital herpes is different, with smaller malaise, and headache were reported by 19 of 20 pa- and superficial erosions often coalescing in a polycyclic tients. Two of them had IgM antibodies to VCA (10%), pattern, and this differential diagnosis can be confirmed and 2 had possible evidence of acute CMV infection. Sum- by genital polymerase chain reaction or culture. mary rather than detailed individual data were pro- A much-debated question is how the EBV reaches the vided; thus, peculiar findings in the 2 patients with as- genital mucosa in AGU. Four modes of transfer of EBV sociated EBV primary infection were not available. Other to the genital mucosa may be discussed. First, potential laboratory findings were nonspecific. The median dura- transmission via genital-genital contact has been hypoth- tion of pain was 10 days, and 15 patients (75%) healed esized,30 given that EBV shedding has been identified in

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 2. Previously Reported Cases of First Flare of AGU Associated With EBV in Female Patients Without Previous Sexual Contact

Lymph HSV EBV Local EBV Age, Features Node Systemic Blood Cell Workup Serologic Workup Duration Source y of AGU Findings Signs Count Findings Findings Findings Treatment of AGU Barnes et al,9 14 2 Painful, ϩ Fever, tonsillitis, Lymphocytosis Serologic and VCA: IgMϩ, Genital EBV: − Cephalexin 70 d 2007 well- (Anterior myalgias, (lymphocyte genital IgGϩ hydrochloride, circumscribed, cervical) fatigue, count, PCR: − naproxen deep, 1- to 2-cm vomiting, 4092/µL); sodium, bilateral labial headaches, AL, 19% prednisone ulcers blurry vision, (20 mg/d) dizziness, cholestatic and cytolytic hepatitis Cheng et al,5 16 Multiple, painful ϩ Fatigue, headache Elevated NA MNT: −; NA None NA 2004 ulcers, 1 cm in (Tender, monocyte VCA: IgMϩ diameter with cervical levels ragged edges and and central granulation inguinal) tissue on labia minora Cheng et al,5 10 Multiple ulcers, 0.3 − Fever, elevated Leukocytosis Culture and MNT: ϩ; VCA: NA Antibiotics NA 2004 to 2.5 cm in transaminase (WBC count, pathological Igϩa diameter level 17 000/µL); study on AL detected lesion biopsy (number NA) specimen: − DeKlotz and 12 Bilateral large, deep, − Fever NA Culture of VCA: IgM−, − None 21 d Frieden,11 pseudo- ulcer: − IgG ϩ 2008 membranous and EBNA: IgG− exudative ulcers on labia minora Groulier 13 Painful ulcer on labia ϩ Fever, headache, Leukocytosis HSV serologic: Strongly NA NA NA et al,13 1986 majora; edema (Bilateral cytolytic (WBC count, weakly ϩ positive MNT: cervical hepatitis 12 800/µL); strongly ϩ; and lymphocytes, VCA: IgMϩ, inguinal) 61%; AL, 12% IgGϩ Hudson and 13 Multiple necrotizing ϩ Fatigue WBC count Culture of MNT and IgM NA Acyclovir NA (Ն25 d) Perlman,14 ulcers with (Bilateral within refer- ulcer: − and IgG VCA sodium, 1998 fibrinous exudates inguinal) ence range; findings cefoxitin on labia minora AL, 5% consistent sodium, with acute amoxicillinϩ MN clavulanate potassium Lampert 13 Pruritic and painful ϩ High fever, Leukocytosis Genital VCA: IgMϩ, Genital Acyclovir, “Few weeks” et al,16 1996 2-cm bluish black (Enlarged myalgias, (WBC count, culture: − IgGϩ; EBNA: culture: − amoxicillinϩ ulcer of left labium and fatigue 11 700/µL); Ig −a; VCA clavulanate minus, covered by swollen lymphocytes, (2 mo later): a dirty adherent cervical) 46%; AL, 10% IgM−, IgGϩ membrane and surrounded by other smaller ulcers Lorenzo and 18 Multiple, large, ϩ Fever Leukocytosis Serologic and MNT and IgM NA Acyclovir, 22 d Robert- painful, (Cervical) (WBC count, direct and IgG VCA ciprofloxacin son,18 2005 hemorrhagic, 5000/µL); fluorescent findings hydrochloride, necrotic, ulcerated AL, 24%; antibody consistent prednisone lesions on labia thrombopenia tests: − with acute minora (platelet count, MN 131 000/µL) McKenna 13 3 Very large, deep ϩ Fever Presence of AL Genital VCA: IgMϩ NA Acyclovir NA et al,19 1994 ulcers on labia (Marked, culture: − minora with vivid general- purple borders ized) Navarro 14 Painful 2-cm ulcer on − Fever, malaise, Within reference HSV tests: MNT: ϩ; VCA: NA Topical fusidic 20 d (no Llanos left labium majus headache range IgM−, IgGϩ IgMϩ, IgGϩ acid relapse et al,20 1996 with soft, (at days 5 during erythematous edge and 60) 16-mo and clean center follow-up) Pelletier 15 Ulcers on labia ϩ Flulike symptoms Leukocytosis Serologic: VCA: IgMϩ, PCR for EBV Macrolide NA (Ͻ28 d) et al,21 2002 minora (Cervical) (fatigue, fever, (WBC count, consistent IgGϩ; EBNA: DNA on chills), cytolytic 6700/µL); with previous IgG− (lately lesion biopsy and cholestatic numerous AL; acquired converted) specimen:ϩ hepatitis thrombopenia immunity (platelet count, (IgM−, IgG) 68 000/µL)

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Lymph HSV EBV Local EBV Age, Features Node Systemic Blood Cell Workup Serologic Workup Duration Source y of AGU Findings Signs Count Findings Findings Findings Treatment of AGU Pelletier 17 Painful ϩ Flulike symptoms Numerous AL; NA VCA: IgMϩ, PCR for EBV Amoxicillin NA et al,21 punched-out– (Cervical) (fatigue, fever), thrombopenia; IgGϩ; DNA on (Ͻ28 d) 2002 appearing ulcers cytolytic anemia (ϩ for EBNA: IgG− lesion with fibrinous hepatitis cold agglutinin) biopsy center on labia specimen: minora ϩ Svedman 14 Extremely painful, − Fatigue, fever, − PCR for HSV VCA: IgMϩ, NA Prednisone 14 d et al,22 deep ulcer on left oral ulcers DNA: − IgGϩ; 2004 labium majus EBNA: IgG− Taylor et al,23 14 Deep, painful ϩ Fatigue, fever Elevated Culture and MNT: −; EBNA PCR for EBV Acyclovir 14 d 1998 kissing-pattern (Tender, lymphocytosis; direct EIA: −; VCA: DNA: ϩ ulcers, 1 cm in generalized) numerous AL fluorescent IgMϩ diameter, on labia antibody majora; central test: − gray slough and vivid purple edge Wilson,24 10 15-mm painful ϩ Fever NA DIF on swab MNT: ϩ NA Acyclovir Ͻ2wk 1993 kissing-pattern (Small (temperature, of ulcers: − ulcers on labia anterior 39.5°C), minora; edema cervical) nausea, anorexia, headache, myalgias

Abbreviations: AGU, acute genital ulcers; AL, atypical lymphocytes; DIF, direct immunofluorescence; EBNA, EBV nuclear antigen; EBV, Epstein-Barr virus, EIA, enzyme immunoassay; HSV, herpes simplex virus; MN, mononucleosis; MNT, monospot test (heterophile antibody); NA, not assessed (or not reported); PCR, polymerase chain reaction; VCA, vival capsid antigen; WBC, white blood cell; ϩ, positive; −, negative. SI conversion factors: To convert lymphocytes and WBCs to ϫ109/L, multiply by 0.001; lymphocyte percentage to a proportion of 1, multiply by 0.01; platelets to ϫ109/L, multiply by 0.001. aThe nature of the immunoglobulin was not specified.

male semen31 and in the uterine cervix.32 Second, trans- that the diagnosis of AGU related to EBV primary infec- mission via oral-genital contact is suggested by previous tion should be based essentially on VCA-IgM results. The reports of long-term salivary shedding of EBV after histopathological examination of the mucosal biopsy infectious mononucleosis and in healthy adults.33,34 specimen performed in 5 of our 13 patients showed only These 2 hypotheses seem unlikely because 92% of the nonspecific inflammatory dermal infiltrates. We there- patients in our series had had no previous sexual con- fore consider this invasive diagnostic method as prob- tact. Third, shedding of EBV in the urine has been ably not relevant in most cases of AGU. shown during and after infectious mononucleosis35 as Primary infection with EBV is a largely underrecog- well as in healthy adults.36 Fourth, a hematogenous nized cause of AGU, leading patients to unnecessary in- spread of EBV-infected lymphocytes14,16,23 or Langerhans vestigations, treatment, and anxiety. Patients should be cell precursors37 has been reported. Furthermore, the informed that this rare form of acute mononucleosis is clinical sequence of systemic signs (fever, asthenia, and self-limiting and seldom relapses. Supportive care pri- prodromic tonsillitis) and genital signs is evocative of a marily aimed at pain relief is indicated in all cases. Sys- hematogenous transfer of EBV to the genital mucosa. temic corticosteroids have been administered by some Overall, even if there is currently no solid evidence to authors for peculiarly painful or long-lasting AGU,9 but definitely promote one of these hypotheses, the urinary evidence-based data on the efficacy-safety balance are and hematogenous routes are the most likely ones and lacking. Despite showing in vitro activity, acyclovir dem- may coexist. Once having reached the genital mucosa, onstrated no clinical benefit in a meta-analysis of 339 pa- the EBV may provoke a cytotoxic immune response, tients with EBV primary infection.39 suggested by the CD8ϩ granzyme-Bϩ T-cell inflamma- Our series of consecutive patients is the first, to our tory infiltrate retrieved in some of our EBV-infected knowledge, to permit an estimation of the rate of EBV patients. primary infection among patients with AGU in the ab- The heterophile antibody (monospot) test is widely sence of STD, although the small size of our series does used, but its sensitivity and specificity are weak. The not allow for a definite estimation. The analysis of the monospot test should systematically be replaced by VCA- present series and of the previous reports5,9,11,13,14,16,18-24 IgM and VCA-IgG tests, which are sensitive and specific yields several messages for the clinician. (1) Acute mono- and emerge early during the course of EBV primary in- nucleosis should always be in a clinician’s differential di- fection.38 Furthermore, in 3 of our 4 patients with EBV agnosis of AGU, especially when there is no context of primary infection, findings of the local workup for EBV sexual transmission and no history of genital aphthosis. were negative, demonstrating the low sensitivity of this (2) Failure to consider causes other than genital aphtho- diagnostic method in this clinical setting. We conclude sis or herpes may expose patients and their family to un-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 necessary investigations, treatments, and stress. (3) The 6. Halvorsen JA, Brevig T, Aas T, Skar AG, Slevolden EM, Moi H. Genital ulcers as initial manifestation of Epstein-Barr virus infection: two new cases and a review symptomatology of AGU is essentially nonspecific; there- of the literature. Acta Derm Venereol. 2006;86(5):439-442. fore, a systematic initial workup is required and should 7. Swaminathan S, Kelley P, Ahern M, Gordon D. Acute cytomegalovirus infection pre- be clinically oriented.5 (4) The physiopathology and eti- senting with severe vulvar swelling. Int J Gynaecol Obstet. 2007;99(2):133-134. 8. Abulafia O, DuBeshter B, Dawson AE, Sherer DM. Presence of cytomegalovirus ology of nonherpetic AGU still constitute broadly unex- inclusion bodies in a recurrent ulcerative vaginal lesion. Am J Obstet Gynecol. plored research fields in which further prospective clini- 1993;169(5):1179-1180. cal and microbiological studies are needed. Further 9. Barnes CJ, Alio AB, Cunningham BB, Friedlander SF. Epstein-Barr virus– associated genital ulcers: an under-recognized disorder. Pediatr Dermatol. 2007; infectious causes of this little-known syndrome may be 24(2):130-134. recognized in the near future. 10. Brown ZA, Stenchever MA. Genital ulceration and infectious mononucleosis: report of a case. Am J Obstet Gynecol. 1977;127(6):673-674. 11. DeKlotz CM, Frieden IJ. Vulvar ulcerations resulting from acute Epstein-Barr vi- Accepted for Publication: May 16, 2008. rus infection. Arch Pediatr Adolesc Med. 2008;162(1):86-87. Author Affiliations: Service de Dermatologie, Pavillon 12. Fett N, Hinshaw M. Multiple painful vaginal ulcerations. Arch Dermatol. 2008;144 (4):547-552. Tarnier, Hoˆpital Cochin (Drs Farhi, Wendling, Avril, Pe- 13. 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