Clinical and Experimental Ophthalmology (2001) 29, 327–329
Case Report Microsporidial keratoconjunctivitis after HAART Adam D Gajdatsy MRCP and Mei-Ling Tay-Kearney FRACO Royal Perth Hospital, Wellington Street, Perth, Western Australia, Australia
ABSTRACT A 44-year-old man presented with bilateral punctate corneal epitheliopathy complaining of worsening discomfort and photophobia over the previous several days. He was HIV positive, had a recent CD4 count of 4 × 106, and had started on highly active antiretroviral therapy (HAART) 14 days prior. Failure to respond to lubricant therapy with worsening of the epitheliopathy over the following week led to corneal biopsy and diagnosis of corneal microsporidiosis. Investigations revealed that he remained anergic and that his CD4 count had not changed. However, his viral load had decreased by at least 0.9 log10 units since HAART initiation. Therapy with albendazole led to complete resolution of his pre-existing symptoms of nasal congestion and epistaxis, as well as all recently occurring ocular signs and symptoms. It was concluded that the microsporidiosis was a pre-existing opportunistic infection, whose presence was unmasked by a form of immune restoration induced by HAART. Key words: albendazole, HAART, immune restoration disease, keratoconjunctivitis, microsporidia.
INTRODUCTION Microsporidia are obligate intracellular parasites, first described in 1857 as parasites of silkworms. Microsporidia are now known to parasitize other invertebrates, fish and mammals including primates. The first verifiable case report of human microsporidiosis was reported in 1959, one of only 11 cases described in presumed immunocompetent individuals. Microsporidial keratoconjunctivitis was first described in a patient with acquired immunodeficiency syndrome (AIDS) in 1990. More than 400 cases of microsporidial infection have since been described in HIVinfected patients.1,2 The use of highly active antiretroviral therapy (HAART; reverse transcriptase inhibitors plus protease inhibitor) in HIV-infected individuals appears to restore pathogenspecific immune responses, which then prevents or results in the regression of diseases caused by opportunistic
pathogens.3–6 However, the possible consequences of immune restoration also include inflammatory disease in tissues where there is a subclinical infection with an opportunistic pathogen. These ‘inflammatory’ diseases may be viewed as immune restoration diseases rather than immunodeficiency diseases.7,8 We report a case of microsporidial keratoconjunctivitis associated with immune restoration after HAART.
CASE REPORT A 44-year-old, HIV-infected white man presented to his immunologist 14 days after commencement of HAART (stavudine 60 mg, didanosine 400 mg, nelfinavir 2500 mg and hydroxyurea 1 g per day), with fevers, epistaxis and photophobia. Urgent ophthalmic assessment followed the same day. His HIV-positive status was established 10 years ago, at which point his CD4 T-cell count was 19% (absolute 361 × 106 cells/L) and he was anergic on skin testing. Prior to this acute presentation he had failed treatment on all available antiretroviral therapy because of multiple drug hypersensitivities, side-effects and also viral resistance. He had been seen at the Eye Clinic at the Royal Perth Hospital for the previous 3 years, with 6-monthly follow up initially. More recently, as part of the study of adefovir dipivoxil (an acyclic nucleoside phosphonate inhibitor of HIV replication) in HIV-infected individuals with CD4 counts less than 100 × 106 (ADHOC study), he was seen on a monthly basis. Ophthalmic findings were essentially unremarkable, excepting that over the previous 18 months fine pigmented deposits were seen on the corneal endothelium. These were thought possibly to be due to repeated dilatation of his brown irides. Eight months prior to this presentation, he started to complain of ‘tired’, dry eyes in association with nasal congestion and postnasal drip. Ocular examination at that time revealed a few punctate epithelial erosions, blepharitis and a dry mouth. Artificial tears with lid scrubs were recommended with relief of his ocular symptoms. In contrast to the above symptoms, this acute presentation showed a man with photophobia, mild conjunctival injection with a moderate number of coarse, greyish corneal
■ Correspondence: Dr Adam Gajdatsy, Eye Clinic, Royal Perth Hospital, Wellington Street, Perth, WA 6000, Australia. Email:
[email protected]
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Figure 1. Left eye at diagnosis demonstrating coarse punctate epithelial erosions typical of microsporidiosis.
epithelial erosions in both eyes (Fig. 1). Visual acuities were 6/9 OD and 6/12 OS with no evidence of intraocular inflammation. He was treated with chloramphenicol ointment and preservative-free artificial tears but his symptoms progressively worsened with development of marked photophobia, red eyes, increased numbers of corneal erosions and visual acuities of 6/36 OU. His immunological work up at this time showed him to still be anergic with no improvement of his CD4 T-cell count (4 × 106 cells/L) since initiation of this episode of HAART. However, it was noted that his viral load fell by at least 0.9 log10 (from ≥ 5.8 log10) for the first time ever on an antiretroviral treatment. A definitive diagnosis of microsporidial disease was made from a corneal biopsy with epithelial debridement. Albendazole (400 mg b.d.) was subsequently started with complete resolution of the ocular symptoms and signs 2 weeks later. Interestingly, his sinus complaints also resolved. Although long-term treatment with albendazole had been planned, it was stopped at 3 months because of worsening hepatitis. Follow up for the 4 months since cessation of albendazole showed no recurrence of disease.
DISCUSSION Microsporidia are obligate intracellular parasites that form a phylogenetic link between prokaryotes and eukaryotes. They are considered to be true eukaryotes, having a nuclear envelope, intracellular membrane system, and chromosomes separated on a mitotic spindle. Like prokaryotes, they have no mitochondria, peroxisomes, or separate 5.8S rRNA, and have prokaryotic small subunit rRNA. Microsporidia have a unique mechanism of infection. The sporoplasm is injected into the host cell via a polar tube which everts from within the thick-walled spore coat. Thereafter, the life cycle varies
Gajdatsy and Tay-Kearney between the different genera of microsporidium. Four genera have been recognized to cause human infection, namely Encephalitozoon, Nosema, Enterocytozoon, and Pleistophora. Of these, Encephalitozoon and Nosema (or Nosema-like) species have been causative agents in human ocular disease. Clinical presentation of ocular microsporidial disease depends on the individual’s immune status. For those with an intact immune system, the clinical picture can be that of a disciform or stromal keratitis with conjunctivitis. With immunodeficiency of any cause, ocular microsporidial disease seems to be confined to the corneal epithelium and conjunctiva.1,2 Treatment of microsporidial eye disease may be medical and/or surgical. Medical treatments described include itraconazole with reports of varying success, topical fumagillin and albendazole. Fumagillin is useful (not available in Australia) but the ocular disease tends to recur when drops are stopped. Albendazole has been reported to have eliminated microsporidial disease but cases are few with limited follow up. Surgical treatment includes epithelial debridement (‘debulking’) although theoretical concerns exist about the possibility that this could increase the risk of corneal stromal involvement. Penetrating keratoplasty has been performed in three of four reported cases of corneal stromal disease with success in two cases.1,9,10 Treatment of HIV-infected patients with antiretroviral therapy often leads to partial reconstitution of the immune system and the restoration of impaired antigen-specific cellmediated immune responses. This process includes restoration of pathogen-specific immune responses. Diseases caused by opportunistic pathogens have been observed to regress after use of HAART; the associated incidences of opportunistic infections are declining. However, immune restoration could also lead to an inflammatory response to a previously subclinical infection. In one retrospective study of patients achieving at least a 1 log10 decline of plasma HIV RNA after HAART, one or more disease episodes occurred in around 25% of patients.11 Most episodes occurred during the first 2 months of therapy when CD4 T-cell counts were increasing. Inflammatory disease related to Cytomegalovirus, Varicella-Zoster virus, Mycobacterium, Hepatitis C virus, cryptococcus and the human papilloma virus have been reported.3,4,12–14 To our knowledge, this is the first report involving microsporidial disease. Immune restoration diseases occur predominantly in severely immunodeficient patients. After treatment with HAART, there is typically an increase in the blood CD4 T-cell count. These are initially memory T cells associated with an increase in the CD4 T-cell receptor repertoire, followed by a rise of naïve CD4 T cells.5,6 This increase may be attributed to a redistribution of cells from lymph nodes or infected tissues. This is, however, a simplified account of how the immune system recovers; additional mechanisms of immune recovery remain to be elucidated. Our patient demonstrated a significant drop in his viral load at the time of his acute presentation, the first drop in his 10-year history of HIV infection. However, we did not
Microsporidial keratoconjunctivitis see a commensurate rise of his CD4 T-cell count. This may be a reflection of the early presentation after HAART, and/or that his T-cell reserves are so depleted that it requires more time for immune recovery to occur, or that no potential for further recovery exists (due to clonal deletions). It seems likely that subclinical microsporidial disease occurred 8 months prior to this acute presentation when he complained of dry and tired eyes together with discharging sinuses. This is the first reported case of ocular microsporidial disease occurring in an HIV-infected individual after HAART initiation. It is most likely that latent corneal disease was unmasked with the reconstitution of the immune system that is seen with potent antiretroviral treatment. It is important to be aware of, treat, or provide prophylaxis for opportunistic infections before starting HAART in severely immunocompromised patients.
ACKNOWLEDGEMENTS ADG wishes to acknowledge first the useful discussions with Simon Mallal and Martyn French on the topic of immune restoration disease. Any inaccuracy or oversimplification is mine. In addition, Matthew Wade’s sterling work as medical photographer is gratefully acknowledged.
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