Cytomegalovirus Infection Associated with Severe Intraocular Inflammation in an HIV Patient: A Case Report

Abstract

This is a report of a case of severe intraocular infammation associated with cytomegalovirus in an untreated HIV+ patient with a marked CD4⁺ T-cell depletion. The atypical presentation shown could confuse and delay the diagnosis. Early suspicion and appropriate treatment (ganciclovir, valganciclovir, HAART) increase the likelihood of a favourable outcome.

Introduction

A wide spectrum of ophthalmic manifestations can be associated with HIV. Beyond them, opportunistic infections stand out as the most frequent eye disorders in the patients. Particularly, cytomegalovirus (CMV) retinitis accounts for an important cause of vision loss among patients with HIV infection [1]. The incidence of CMV retinitis decreased substantially in the highly active antiretroviral treatment (HAART) era. In a cross-sectional analysis of longitudinal study of ocular complications of AIDS (LSOCA) data at enrolment, the incidence rate was estimated to be 5.6/100 person-years. The incidence rate observed during follow-up in LSOCA was 0.4/100 person-years [2]. There are definite risk factors for the development of an active CMV eye infection, especially a low CD4⁺ T-cell count, with cutoff values of the latter being set at 50 to 100 cells/mm³, although some variations in these figures can be found between authors [3]. As a consequence of such low CD4⁺ T-cell counts, CMV active infections typically occur with little inflammation.

We report the case of a patient with an untreated CMV–HIV coinfection who displayed high intraocular inflammation despite marked immunosuppression. We underline that this completely unexpected presentation could delay diagnosis and management of a serious ophthalmological disease.

Case report

A 39-year-old male patient complained of a 3-week history of decreased visual acuity (VA) in the right eye (OD), worsening over the previous week. He had been diagnosed of HIV infection 3 years before, and despite not having sought follow-up care or treatment, his condition had nonetheless remained subclinical. In addition, he had a past history of 2 treated episodes of primary syphilis.

His best-corrected VA was 20/400 in OD and 20/20 in the left. Along with anterior chamber inflammation, physical examination revealed abundant posterior granulomatous keratic precipitates, and vitreous haze grade 4 following the Standardization of Uveitis Nomenclature (SUN) working group (Figure 1), which impaired a detailed fundus examination. Focal retinal lesions were apparent in OD throughout the clinical course. Left eye showed no relevant abnormalities. Serological studies were conducted, yielding positive immunoglobulin (Ig)G and IgM CMV antibodies, while polymerase chain reaction (PCR) amplification revealed 70,689 CMV copies/ml at the aqueous fluid. Peripheral blood lymphocyte count was of 600 cells/mm³ (60 CD4/mm³; CD4/CD8: 0.14). The HIV load was 1,857,000 copies/ml. Additional potential infections were ruled out, including toxoplasmosis, untreated active syphilis, tuberculosis and the herpesviridae (herpes simplex virus [HSV], varicella zoster virus [VZV] and Epstein–Barr virus [EBV]), with specific indirect tests.

Figure 1

Vitreous haze grade 4 in the right eye from the onset

Induction therapy with intravenous ganciclovir (10 mg/kg/day) was administered for 14 days, then switched to a 45-day course of oral valganciclovir (1,800 mg/day) in combination with a 15-day tapering regimen of topical corticosteroids. The patient was placed on HAART (600 mg abacavir, 50 mg dolutegravir, 300 mg lamivudine). At 4 months of follow-up the outcome was favourable.

Discussion

CMV is a double-stranded DNA virus belonging to the Herpesviridae family. The cellular immune response to CMV relies on both the adaptive and the innate immune systems. Instead of being cleared away following primary infection, the virus remains latent in granulocytes, macrophages and dendritic cell precursors. CMV maintains this niche through the limited expression of molecules with immune evasion functions, which allow it to avoid detection by cytotoxic cells [4]. One of the hallmarks of CMV infection is a demonstrable expansion of CD8⁺ T-cells. However, CMV-specific CD8⁺ T-cells appear to be dysfunctional, since their recruitment and activation do not eliminate or effectively control CMV replication [5]. In addition, in spite of being globally considered as the most important source of host defence against CMV, there is increasing evidence supporting that besides CD8⁺ T-cells, other immune cells, such as CD4⁺ T-cells, gamma/delta (γ/δ) T-cells, natural killer (NK) cells and regulatory T cells (Tregs) also play a role [4].

The CD4⁺ T-cell depletion evoked by HIV may promote transition from latency to the lytic phase of CMV infection, since the suppression of this line of defence is associated with a large-scale activation of granulocytes, macrophages and dentritic cells, all of which act as CMV reservoir. In the context of CD4⁺ T-cell depletion and possibly in Treg cells as well, these innate cells may bear an enhanced capacity to induce autoreactive T-cell co-stimulation.

Nearly all HIV carriers are coinfected with CMV. This coinfection is characterized by the up-regulation of different circulating proteins, the expansion of CD8⁺ T-cells, and a reduced CD4:CD8 ratio, which correlates with an increased morbidity and mortality in this population [5].

In patients who show severe immunosuppression, CMV infection can lead to an array of serious diseases, CMV retinitis being a prominent one. Although its incidence has decreased in the era of HAART [2], CMV retinitis continues to affect patients with late-stage HIV. This can be due to the current increased survival rates of HIV patients as also to antiretroviral drug resistance [3].

CMV retinitis mostly occurs in patients with CD4⁺ T-cell counts <100 cells/mm³ and shows a higher prevalence in males between the second and fifth decades of life. The disease is usually bilateral and presents with a substantial loss of VA in the affected eye/s [1,3]. All these traits were found in our patient, except for a bilateral involvement. Patients without HIV infection typically display high intraocular inflammation already from the onset of the condition. On the other hand, HIV carriers characteristically have an insidious onset of symptoms [6,7] while the initiation of HAART usually leads to overt inflammation and a paradoxical worsening of the condition in relationship with the reconstitution of the immune system [8,9]. This entity is known as immune recovery uveitis (IRU) and typically targets those HIV-infected patients who prior to HAART initiation have a deep immunosuppression status. The prevalence of IRU among these patients has been estimated in 15.5% in the United States, 25% in India and 10% in southern China [1,9]. Intriguingly, the clinical course of our patient was quite the opposite, since his initial status of low CD4⁺ T-cell counts was associated with high intraocular inflammation, while the latter subsided in spite of introduction of HAART.

At the time of assessment, after a 3-week history of visual symptoms, intense vitritis and retinitis were found, and considering the past history of untreated HIV, workup included CD4⁺ T-cell count indirect microbiological tests and aqueous humour PCR, these assays being conclusive for a CMV active intraocular infection. In addition, other possible infections were consistently ruled out, further supporting the diagnosis. Upon HAART initiation, the normalization of CD4⁺ T-cell counts and/or functions probably accounted for the return of CMV to latency, and with it to a total resolution of the symptoms. In spite of the rarity of clinical presentation, both the response to therapy and the outcome further support CMV as the aetiological agent of this case of retinitis.

There are some reports of chronic necrosis of the retina resulting from CMV eye infection in patients with some degree of immunodeficiency, in relationship with advanced age, diabetes mellitus, use of corticosteroids or immunosuppressors [10]. However, this condition had not until now been reported in immunocompromised patients with HIV. Retinitis of an aggressive course was also described in a patient coinfected with VZV/HSV and HIV. The patient developed acute renal necrosis and progressive outer retinal necrosis, a presentation which illustrates the variability of the host response to these harmful agents [11].

In the case of coinfection, this response largely depends on the host characteristics. The inflammatory phenotype exhibited by our patient might be explained by the ability of HIV to induce cell death of infected cells, including monocytes and dendritic cells, which also act as reservoir for CMV. These circumstances can lead to the activation of the lytic phase of CMV or its detection by virus-specific CD8⁺ T-cells, both of which would trigger a vigorous response from the preserved immune system [12].

In summary, the wide spectrum of clinical manifestations potentially associated with CMV should be taken into account in HIV-infected individuals, since both an early diagnosis and an appropriate treatment increase the likelihood of a favourable outcome. In addition, it is important that these patients undergo ophthalmological follow-up during the recovery of immune system with HAART to watch for the development of IRU.