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 Table of Contents  
CASE REPORT
Year : 2023  |  Volume : 13  |  Issue : 1  |  Page : 88-92

Steroid-responsive unilateral keratouveitis following systemic treatment in a patient with human immunodeficiency virus and leishmaniasis


Department of Ophthalmology, University of Southern California, Los Angeles, California, USA

Date of Submission17-Sep-2022
Date of Acceptance05-Dec-2022
Date of Web Publication20-Feb-2023

Correspondence Address:
Dr. Kristina Voss
University of Southern California, Los Angeles, California
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjo.TJO-D-22-00130

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  Abstract 


Ocular leishmaniasis, a rare form of vector-borne parasitic infection, can affect the adnexa, retina, uvea, and cornea. Coinfection with human immunodeficiency virus (HIV) and Leishmania may be a distinct clinical entity as the pathogens act synergistically, enhancing each other's pathogenicity, and leading to more severe forms of the disease. Ocular leishmaniasis in the setting of HIV coinfection most commonly causes anterior granulomatous uveitis, for which the etiology can be either active ocular infection or posttreatment inflammatory phenomenon. Keratitis is not considered to be associated with HIV but has rarely been seen from direct parasite invasion or in association with miltefosine. The judicious use of steroids in the treatment of ocular leishmaniasis is critical as steroid use is paramount to the treatment of uveitis associated with posttreatment inflammatory phenomenon but can worsen the prognosis when given in the setting of active, untreated infection. Here, we present a case of unilateral keratouveitis in a leishmaniasis and HIV-coinfected male following completion of systemic antileishmanial therapy. The keratouveitis completely resolved with only the addition of topical steroids. The rapid resolution with steroids suggests that keratitis, not only uveitis, can be an immune-mediated phenomenon in post- or ongoing-treatment individuals.

Keywords: Human immunodeficiency virus, keratitis, miltefosine, ocular leishmaniasis, steroid, uveitis


How to cite this article:
Su E, Lu JE, Voss K. Steroid-responsive unilateral keratouveitis following systemic treatment in a patient with human immunodeficiency virus and leishmaniasis. Taiwan J Ophthalmol 2023;13:88-92

How to cite this URL:
Su E, Lu JE, Voss K. Steroid-responsive unilateral keratouveitis following systemic treatment in a patient with human immunodeficiency virus and leishmaniasis. Taiwan J Ophthalmol [serial online] 2023 [cited 2023 Mar 25];13:88-92. Available from: https://www.e-tjo.org/text.asp?2023/13/1/88/370019




  Introduction Top


Leishmaniasis, caused by the protozoan Leishmania parasite, is a vector borne, potentially life-threatening, zoonotic disease that is transmitted through sand fly bite to its human host.[1] Every year, over one million new cases occur worldwide, with numbers concentrated mainly in the tropics, subtropics, and Southern Europe. The disease entities include diffuse cutaneous (DCL), mucocutaneous (MCL or espundia), visceral (VL or Kala-azar), and postkala-azar-dermal (PKDL) leishmaniasis. DCL syndrome involves widespread cutaneous rashes. MCL is an extension of the former syndrome, but also includes nasopharyngeal mucous membrane involvement. VL is leishmaniasis with internal organ involvement, whereas PKDL consists of bullous maculopapular rashes on the face, upper chest, and hands, following systemic antileishmanial VL treatment. However, the emergence of Leishmania and human immunodeficiency virus (HIV) coinfection has given rise to more atypical, relapsing, and severe disease manifestations.[2],[3],[4],[5],[6],[7],[8],[9],[10] Attributing this to a synergistic relationship between the pathogens and seeing concurrent leishmanial syndromes sometimes including atypical infection sites such as the eye and some specialists even consider it a distinct clinical entity.

Ocular leishmaniasis is a rare, even in endemic regions. A systematic review of the literature performed by Mignot et al. (1948–2020) found only 57 total reports.[11] The level of evidence is case reports and case series only. Adnexal involvement is the most reported presentation and may appear as conjunctival lesions, chronic blepharitis, pterygium, and hordeolum. Retinal involvement has only been reported in the context of thrombocytopenia seen in VL. It presents as retinal hemorrhage or whitening, cotton wool spots, or vascular sheathing or tortuosity. Uveal involvement is considered a disease of the immunocompromised, especially among HIV + patients. Uveitis usually presents as a bilateral anterior granulomatous uveitis and can represent active leishmanial infection or posttreatment immune reconstitution following highly active antiretroviral therapy (HAART) or inflammatory phenomenon following systemic antileishmanial therapy.[11],[12],[13],[14],[15] Biomicroscopic findings alone cannot differentiate between these conditions, therefore correlating time of onset with treatment course, as well as possible culture, is important. Topical steroid therapy can result in resolution of uveitis brought on by immune mechanism, however when given in the setting of active infection, blindness occurs.[16],[17]

Primary corneal leishmaniasis is the rarest of the ocular leishmanial manifestations, with only six reports (22 cases) in the literature,[11],[18],[19],[20] and only one of which was associated with HIV. The most common presentation was aggressive ulcerative keratitis which resulted in perforation if untreated. Treatment with systemic and topical, intracameral or intrastromal antileishmanial therapy such as amphotericin was reported, and steroids were thought to play a minor role.

Keratitis and scleritis have also been reported in the setting of antileishmanial treatment with miltefosine.[19],[20],[21] This association is being monitored by a pharmacovigilant expert group within the World Health Organization. There is insufficient evidence to establish a causal association with miltefosine currently. Mechanisms involving inflammatory response to parasite death as well as an adverse drug reaction from miltefosine itself, have been proposed.


  Case Report Top


The University of Southern California Institutional Review Board approved our application (HS-22-00650) for this retrospective case. The study was determined to be exempt from 45 CFR 46 according to 46.104(d) as a category.[4] Patient consent for HIPPA authorization was also obtained.

The patient is a 38-year-old HIV + male, well controlled (CD4 count of 213 cells/mm3 with an undetectable viral load) on dolutegravir and emtricitabine-tenofovir, without any prior ocular problems. He presented with a nonulcerative papulonodular hypopigmented rash with lesions scattered along the bilateral upper and lower extremities, trunk, and abdomen [Figure 1]. H and E staining of the cutaneous biopsy showed Leishmaniasis chassis and infantum. Thrombocytopenia and splenomegaly were also noted. The patient immigrated to the US from Nicaragua at the age of 20 and he has remained in the US since his arrival. The patient was treated with intravenous amphotericin B liposome (7 of 9 doses) and then lost to follow-up. He presented a year later with the same papulonodular rash consistent with cutaneous leishmaniasis. He was retreated with amphotericin (14-dose course) and miltefosine for a 28-day course. Two days after stopping miltefosine, he developed progressive left eye redness, pain, and photophobia.
Figure 1: Diffuse hypopigmented papulonodular rash. Cutaneous biopsy showed Leishmaniasis chassis and infantum

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On day 7 of his symptoms, visual acuity declined to count fingers in the affected left eye. Biomicroscopy showed unilateral 3+ conjunctival and ciliary injections, corneal peripheral haze with focal areas of whitening without epithelial loss or ulceration, and 1+ anterior chamber cell [Figure 2]. No vitreoretinal involvement was noted; however, there was a shallow temporal choroidal effusion of the left eye. Anterior chamber paracentesis was performed for polymerase chain reaction (PCR) analysis for leishmaniasis. No corneal scrapings were performed since the epithelium was intact. Additional infectious workup included HZV aqueous PCR, serum RPR/FTA, QuantiFERON Gold, and serum VZV. All tests were found to be noncontributory. HIV monitoring laboratories revealed a rise in the HIV viral load to 10,500 copies/mL and a decline in CD4 count to 213 cells/mm3. No changes in medications or compliance were noted at that time.
Figure 2: Slit-lamp photographs of the left eye with conjunctival injection, ciliary flush, and corneal infiltrates at the limbus. The epithelium is intact, and the findings presented 7 days after the start of redness, pain, and photophobia

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Cautious initiation of topical steroid (prednisolone acetate 1%) every 2 h and cycloplegic (cyclopentolate 1%) three times per day was done under close monitoring and with the plan to change to topical amphotericin if any worsening occurred. The patient responded rapidly to the application of topical steroids with complete clearing of corneal infiltration and resolution of anterior uveitis [Figure 3]. The visual acuity returned to 20/20 by the Snellen chart. Ocular quiescence has remained off steroids for 2 years even though concurrent cutaneous and visceral disease did recur.
Figure 3: Slit-lamp photograph of the affected left eye showing complete resolution of limbal infiltrates, conjunctival hyperemia, and anterior chamber inflammation following topical steroid therapy

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  Discussion Top


Leishmaniasis and HIV coinfection may represent its own distinct clinical entity. This was first seen during the HIV pandemic when leishmaniasis resurged and atypical presentations such as overlapping forms and ocular findings such as uveitis were reported. Both pathogens target macrophages and dendritic cells, which enhance each other's pathogenicity. Specifically, HIV enhances Leishmanial uptake through CD91/LRP-1 receptors and increased cellular growth.[5] Leishmaniasis, in turn, increases pro-inflammatory cytokine interleukin (IL)-6 and tumor necrosis factor-alpha secretion, thus increasing the size of the CD4+ cell pool for HIV.[2],[3],[4],[5],[6],[7],[8],[9],[10] This immunocompromised state is an opportunity for both pathogens to flourish and was evident in our case as HIV viral load rose and concurrent cutaneous and visceral leishmaniasis occurred. In this immunocompromised state, ocular parasitic infiltration can occur. It is most commonly seen in the uvea, frequently necessitates intracameral or intravitreal amphotericin B therapy, and carries a poor prognosis. Keratitis in the setting of concurrent HIV infection is rare and is presumed to represent parasitic infiltration, again mandating local antileishmanial therapy. There is only one other report of keratitis in an HIV-coinfected individual. That patient presented with bilateral keratouveitis due to parasitic infiltration as both aqueous and corneal scraping were PCR positive for Leishmania.[18] This occurred while the patient was on systemic antileishmanial therapy, therefore local therapy with intrastromal and intracameral amphotericin was given.

Inflammatory phenomena are also seen in coinfected individuals with both postantileishmanial and post-HAART therapies.[11],[12],[13] Leishmania death triggers IL-2 and IFN-y production, which stimulates macrophage nitric oxide and reactive oxygen intermediates, thus leading to a transient state of increased inflammation that should subside during the recovery phase.[10] Reports of uveitis in patients on HAART with CD4 count recovery support an immune-reconstitution etiology.[12],[13] The temporal relationship with uveitis developing days to months after treatment, as well as the clinical response to steroids, supports this proposed mechanism. While steroids are mandated in posttreatment uveitis, antileishmanial therapies are considered the cornerstone for the treatment of keratitis, with steroids playing a supporting role.

Unrelated to HIV coinfection, there have been reports of keratitis, scleritis, and uveitis associated with miltefosine use, and this possible relationship is being investigated.[19],[20],[21] Initially developed as an oral antineoplastic drug, miltefosine induces apoptosis in Leishmania through currently unknown mechanisms,[22],[23] and it is the only available oral antileishmanial medication at this time. While causality for ocular manifestation has not been established, pharmacologic and immune mechanisms have been proposed. A Bangladeshi study[20] suggested miltefosine's long half-life (31 days) and amphophilic properties lead to the formation of phospholipid complexes in the corneal stroma and subsequent trapping within lysozymes. Ocular findings were found 7–10 weeks following initiation of miltefosine therapy[21] and 20–84 days in another case series.[20] Immediate cessation of the drug, along with topical steroid therapy, led to positive responses.

Our case of keratouveitis in the setting of HIV and Leishmania coinfection is unusual due to the presence of corneal infiltrates that responded well to topical steroid therapy. While steroid-responsive immune-mediated uveitis in the setting of coinfection has been reported, the role of steroids in the presence of corneal infiltrates is not clear. The active infection could not be ruled out by aqueous PCR; however, the positive response to topical steroid therapy, as well as reports of disease progression when steroids are given in the setting of parasitic infiltration, support a case of posttreatment inflammatory phenomenon secondary to leishmanial death for our case. Keratouveitis secondary to miltefosine use may also be another possibility given the proximity of onset (2 days after completing the 28-day course). The delay in the presentation of keratouveitis following miltefosine therapy suggests it is more likely due to inflammation from parasite death rather than drug deposition.

In summary, we report a case of steroid-responsive keratouveitis in the setting of post-HIV and leishmaniasis treatment, suggesting immune-mediated mechanisms can present as corneal infiltrates.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors declare that there are no conflicts of interests of this paper.



 
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[PUBMED]  [Full text]  
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Van Os L, Cnops L, Van Esbroeck M, Dhubhghaill SN, De Keizer RJ, Asselman V, et al. Slowly progressive keratouveitis in a patient with known systemic leishmaniasis and HIV. Ocul Immunol Inflamm 2015;23:248-51.  Back to cited text no. 18
    
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