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Chronic Vulval Ulceration - Another Immune Reconstitution Inflammatory Syndrome?

Posted on: Wednesday, 29 June 2005, 09:00 CDT

Summary: We describe a patient who developed intractable chronic vulval ulceration that we believe was related to immune reconstitution following treatment of HIV infection with highly active antiretroviral treatment (HAART). Immune reconstitution inflammatory syndrome should be considered in the differential diagnosis of unexplained vulval ulceration that arises after starting HAART.

Keywords: vulval ulceration, HIV, immune reconstitution inflammatory syndrome

Introduction

Immune reconstitution inflammatory syndrome (IRTS) is a presumed cause of genital ulceration in HIV-positive men after starting highly active antiretroviral treatment (HAART).1 We describe a patient with chronic vulval ulceration that was unexplained despite extensive investigation and in whom the features suggested a manifestation of IRIS. Vulval ulceration caused by IRIS has not been described previously.

Case report

A 35-year-old black female student from Zimbabwe was admitted to hospital with pulmonary tuberculosis and tested positive for HIV antibody. The CD4 lymphocyte count was 250/mm^sup 3^ and HIV viral load 20,000 copies/mL (Roche Amplicor assay). She was treated with rifampicin, isoniazid, ethambutol, pyrazinamide and pyridoxine, and also started zidovudine 300mg/lamivudine 150mg (Combivir) one tablet twice daily and efavirenz (800 mg nocte while taking rifampicin; 600 mg nocte thereafter). She completed a six-month course of antituberculosis treatment.

The medication was well tolerated and the clinical, virological and immunological responses were excellent, with a sustained reduction in viral load to <50 copies/mL and a gradual rise in CD4 count to 1230 cells/mm^sup 3^ over 21 months.

At presentation, small superficial ulcers were present in the natal cleft, suggestive of resolving herpes simplex virus (HSV) lesions; however, HSV antigen was not detected. The ulcers healed without treatment and did not recur. Six months after starting HAART, she complained of a clear vaginal discharge with dysuria, and examination revealed a 2 cm superficial anterior vulval erosion involving the urethral meatus and producing a serous exudate. Over subsequent months, the area of non-tender ulceration surrounded the urethra and extended intravaginally over the anterior vaginal wall (Figure 1). She was otherwise well and the rest of the physical examination was normal. There was no previous history of oral or vulval ulceration, ocular symptoms or skin lesions.

The differential diagnosis included chronic HSV infection, donovanosis, fixed drug eruption, circinate vestibulitis, pemphigoid, pemphigus and an IRIS.

A test for HSV antigen from the ulcer was positive on one occasion, four weeks after the ulcer appeared, and thereafter repeatedly negative. HSV was not detected by viral culture. Syphilis serology (enzyme linked immunosorbent assay, Venereal Disease Research Laboratories and Treponema pallidum haemagglutination assay) was negative. A group B beta-haemolytic streptococcus was isolated from a swab from the ulcer on one occasion, of uncertain significance; there was no other bacterial growth. Two biopsies were taken at different times, which showed a non-specific inflammatory infiltrate composed largely of plasma cells. Modified Giemsa and Warthin-Starry staining were negative for Donovan bodies and spirochaetes; there was no evidence of neoplasia, HSV inclusions or other viral cytopathic features. Cervical smears showed persistent borderline changes and subsequently mild dyskaryosis; one cervical smear was reported to show features suggestive of HSV. Colposcopy revealed an area of mild cervical acetowhitening, from which a biopsy revealed cervical intraepithelial neoplasia-2 (CIN-2) with wart virus changes. The relevant pharmaceutical company had received no reports of genital ulceration in patients taking efavirenz.

Treatment with oral aciclovir, famciclovir, co-amoxiclav, metronidazole, azithromycin and topical 2% clindamycin cream was unsuccessful. We did not try thalidomide because the patient was of childbearing age and sexually active. Some improvement was observed after application of high-potency topical steroid (clobetasol 0.05% cream [Dermovate]) and moderate-potency topical steroid (Trimovate cream [clobetasone 0.05%, oxytetracycline 3%, nystatin 100,00OU/ g]), without resolution of the ulceration. Oral prednisolone 40 mg daily was started 10 months after onset of the lesion and reduction in the size of the lesion was observed, without complete resolution. Oral steroids were continued for a further eight months during which the dose was gradually reduced to the minimum required to prevent worsening (10mg daily). Diflucortolone valerate 0.3% oily cream (Nerisone forte) and potassium permanganate soaks (1:1000 for 15min daily) were also applied. The area healed very slowly; complete resolution was recorded approximately two years after the ulcer had appeared.

Figure 1 Chronic vulval ulcer surrounding the urethra

Discussion

Genital ulcers in HIV-positive women are usually short lived and mostly idiopathic or aphthous (60%); identified causes include HSV, syphilis and chancroid.2 Chronic vulval ulceration in this context is uncommon and less well understood; causes include chronic HSV infection, cytomegalovirus, M. tuberculosis, and neoplasia.3,4 Chronic vulval ulceration in HIV-positive women may be idiopathic and intractable.3 The role of HIV in the direct causation of acute and chronic genital ulcers is uncertain.

IRIS was first recognized in 1995 and may cause a variety of clinical manifestations including ocular inflammation and visual impairment in patients with CMV retinitis, lymphadenopathy in patients with mycobacterial infection and respiratory deterioration during treatment of Pneumocystis carinii pneumonia.5 Onset of symptoms is generally one to 12 weeks after introduction of HAART. It has been difficult to prove definitively that IRIS is the cause of these syndromes. The aetiology is believed to be an augmented inflammatory response reflecting a restoration of pathogen-specific immune responses, rather than reactivation of the initial infection.5,6

Chronic genital ulceration attributed to IRIS has been reported in three HIV-positive Ugandan men with an AIDS diagnosis and genital ulcerations four weeks to six months after starting HAART. All had a previous history of genital HSV, and the authors postulated that partial restoration of immunity to HSV that would enhance the immune response, but not clear the virus, resulted in a hypersensitivity- type response. The cases differed from our patient in that HSV was isolated from the genital ulcers; intravenous foscarnet followed by topical cidofovir were used.1

In our patient, the cause of chronic vulval ulceration in an unusual distribution, unremitting for more than two years, defied extensive microbiological and histological investigation. We believe the transient identification of HSV in the ulcer and on a cervical smear, the timing of the onset after starting HAART, the chronicity of course and gradual response to topical and systemic steroids suggest the diagnosis of IRIS, possibly directed at HSV antigens.

Acknowledgements: We thank Dr Sallie Neal, Dr Valerie Walkden and Miss Deborah Sumner for their help with clinical management and Dr David Hawkins for helpful discussion.

References

1 Fox PA, Barton SE, Francis N, et al. Chronic erosive herpes simplex virus infection of the penis, a possible immune reconstitution disease. HIV Med 1999;1:10-8

2 Clark R, Anderson J. Idiopathic genital ulcer disease in an HIV- infected woman. AIDS Patient Can STDs 1998;12:819-23

3 LaGuardia KD, White MH, Saigo PE, Hoda S, McGuiness K, Ledger WJ. Genital ulcer disease in women infected with human immunodeficiency virus. Am J Obstet Gynecol 1995;172:553-62

4 Covino JM, McCormack WM. Vulvar ulcer of unknown etiology in a human immunodeficiency virus-infected woman: response to treatment with zidovudine. Am J Obstet Gynecol 1990;156:116-18

5 Shelburne III SA, Hamill RJ. The immune reconstitution inflammatory syndrome. AIDS Rev 2003;5:67-79

6 French M, Lenzo N, John M, Mallal S, Price P, Flexman J. Immune Restoration Disease after Treatment of Immunodeficient HIV-infected Patients with Potent Anti-retroviral Therapy. Geneva: 12th World AIDS Conference 1998. (Abstract 340/22323)

(Accepted 6 April 2004)

V Reddy Dip GUMed and G A Luzzi DM FRCP

Genitourinary Medicine, Wycombe Hospital, High Wycombe HP11 2TT, UK

Correspondence to: Dr V Reddy

Email: luzg@wycgu.demon.co.uk

Copyright Royal Society of Medicine Press Ltd. Jun 2005

Source: International Journal of STD & AIDS

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