HHV-6B- and HHV-7-associated choroiditis secondary to acute myelogenous leukemia: a case report

Abstract

We report a case of human herpes virus 6 (HHV-6)- and human herpes virus 7 (HHV-7)-associated choroiditis in an immunocompromised woman. A 42-year-old Chinese woman with a history of acute myelogenous leukemia presented with blurred vision and black floaters in her right eye. Anterior segment examination findings were normal. Ophthalmoscopic examination revealed a subretinal lesion in the superonasal peripapillary region with several punctate hemorrhages. Optical coherence tomography showed a crater-like choroidal protuberance, associated with retinal pigment epithelium rupture and full-thickness retinal edema in the involved area. Indocyanine green angiography demonstrated a broad hypofluorescent lesion in the choroid. The patient was diagnosed with choroiditis. Subsequently, metagenomic next-generation sequencing revealed HHV-6B and HHV-7 DNA in the aqueous humor. Therefore, antiviral therapy was initiated. The patient experienced resolution of all symptoms and signs after treatment with intravenous foscarnet and oral acyclovir. The findings in this case indicate that HHV-6 and HHV-7 can cause ocular infection, particularly in immunocompromised patients.

Introduction

Human herpesviruses 6 and 7 (HHV-6/7) are members of the Roseolovirus genus within the Betaherpesvirinae subfamily. There are two subtypes of HHV-6: A and B. HHV-6B causes most primary infections in early childhood, whereas HHV-6A and HHV-7 are acquired later through asymptomatic infection.¹ The primary infection causes roseola infantum, a common exanthematic disease in infants that is generally mild. HHV-6/7 can establish lifelong latency in human hosts after the initial infection; their reactivation (particularly in immunocompromised patients), either spontaneously or by opportunistic infections, may lead to serious complications. ¹ The most common manifestations of HHV-6/7 are neurological disorders (i.e., encephalitis, multiple sclerosis, and neurocognitive impairment), highlighting the neurotropism of these viruses. ² HHV-6/7-associated pneumonitis, hepatitis, and colitis have also been reported.^3–5 Although intraocular involvement of HHV-6 has been reported in a few cases,^6–9 HHV-7 infections have not been documented. Here, we report a case of choroiditis caused by concurrent reactivation of HHV-6B and HHV-7 in an immunocompromised woman. Written informed consent was obtained from the patient for publication of this case report, and the report complies with the CARE guidelines. ¹⁰ This study was approved by the Ethics Committee of Nanfang Hospital, Southern Medical University.

Case report

A 42-year-old woman with a history of acute myelogenous leukemia presented with blurred vision and black floaters in her right eye, which had begun 5 days prior. Initial examination of the affected eye revealed Snellen visual acuity of 20/25 and a quiet anterior chamber without anterior uveitis or pseudohypopyon. Dilated fundus examination showed mild vitritis, and retinal examination showed an oval-shaped subretinal lesion in the superonasal peripapillary region, surrounded by several punctate hemorrhages. Examination of the patient’s left eye was unremarkable; there were no obvious abnormalities and the Snellen visual acuity was 20/20 (Figure 1a). Enhanced depth imaging optical coherence tomography (EDI-OCT) did not reveal any macular abnormalities. However, fundoscopy revealed a crater-like choroidal protuberance and neurosensory retinal detachment at the site of a yellow-white lesion; these findings were associated with retinal pigment epithelium rupture and full-thickness retinal edema (Figure 1b). Moreover, EDI-OCT showed hyperreflective foci consistent with a diagnosis of vitritis.

Figure 1.

Fundoscopy demonstrated an oval-shaped subretinal lesion, surrounded by several punctate hemorrhages in the superonasal peripapillary region of the right eye. The left eye was completely unaffected (a). Optical coherence tomography revealed a crater-like choroidal protuberance, associated with retinal pigment epithelium rupture and full-thickness retinal edema (b). Asterisks (*) indicate lesions.

A review of systemic medical history confirmed that the patient had been diagnosed with acute myelogenous leukemia 2 months prior to the ocular symptoms. Complete blood count analysis had revealed a white blood cell count (WCC) of 1.15 × 10⁹/L, red blood cell count (RCC) of 1.79 × 10¹²/L, and platelet count of 108 × 10⁹/L. The patient had undergone two courses of chemotherapy (cytarabine plus idarubicin) and achieved complete remission with improved complete blood count (WCC, 5.79 × 10⁹/L; RCC, 2.88 × 10¹²/L; and platelet count, 346 × 10⁹/L). However, 1 week before the onset of ocular symptoms, myelosuppression from chemotherapy agents had led to severe pulmonary edema and infectious shock. Despite repeated blood cultures, no obvious causative microorganisms were identified. Subsequently, the patient received empirical antibiotic therapy involving a combination of meropenem (1.0 g, every 8 hours; Sumitomo Dainippon Pharma, Osaka, Japan) and micafungin (50 mg, daily; Astellas Pharma, Tokyo, Japan) to target potential infections. The patient had provided written and verbal informed consent for treatment. After 1 week of continuous treatment, the patient’s symptoms had considerably improved, including a reduction of pulmonary edema and a decrease in various indices of infectious activity.

After consideration of the patient’s systemic medical history, fluorescein angiography was conducted. The results showed nummular lesions with early hypofluorescence, followed by an extensive area with late hyperfluorescence (Figure 2a, b). Indocyanine green angiography revealed a broad hypofluorescent lesion in the choroid (Figure 2c). During the subsequent systemic examination, complete blood count analysis indicated substantial decreases in WCC (0.03 × 10⁹/L), hemoglobin (75 g/L), and platelet count (12 × 10⁹/L), possibly explaining the retinal hemorrhage. Serologic tests confirmed the absence of human immunodeficiency virus, herpes simplex virus, varicella zoster virus, cytomegalovirus, and Epstein–Barr virus. However, serologic tests showed that hepatitis B surface antigen- and Treponema pallidum-specific antibodies were present. Considering the potential for fungal chorioretinitis secondary to systemic infection, metagenomic next-generation sequencing (mNGS) of intraocular fluid was suggested, but the patient declined this option. Therefore, she was administered empirical antifungal therapy with oral voriconazole (0.2 g, daily; Pfizer, New York, NY, USA); there were no signs of improvements over the following 3 weeks.

Figure 2.

Early (a) and late (b) phases of fluorescein angiography showed lesions with early hypofluorescence, following by an extensive area with late hyperfluorescence. Indocyanine green angiography (c) revealed a broad hypofluorescent lesion in the choroid. Asterisks (*) indicate lesions.

Subsequently, the patient returned with an extended shadow in the right eye, along with a mild anterior chamber reaction; OCT revealed a more aggressive choroidal lesion, as well as more extensive vitritis and retinitis (Figure 3). At that time, anterior chamber paracentesis was performed to obtain samples for mNGS; the analysis identified genomic DNA from HHV-6B and HHV-7. Thus, the patient was diagnosed with HHV-6B- and HHV7-associated choroiditis. Treatment comprised intravenous injection of foscarnet (3.0 g, every 8 hours; Clinigen Healthcare, London, UK) for 1 week and oral administration of acyclovir (0.4 g, every 8 hours; Qidu Pharma, Zibo, China) for 1 month. Over the following 3 months, there was clinically significant improvement in the choroidal lesion and subsequent resolution of chorioretinal inflammation (Figure 4a–c). Additionally, the patient’s Snellen visual acuity improved to 20/20 and the floaters entirely disappeared.

Figure 3.

Optical coherence tomography revealed a more aggressive choroidal lesion, along with more extensive vitritis and retinitis in the right eye. Asterisks (*) indicate lesions.

Figure 4.

Fundoscopy (a) and optical coherence tomography (b) revealed an atrophic and stabilized choroidal lesion in the right eye. Optical coherence tomography showed a normal fovea throughout the course of disease (c). Asterisks (*) indicate lesions.

Discussion

Latent HHV infection is ubiquitous, with 95% seroprevalence in most populations. After resolution of the primary infection, HHV can remain latent in lymphocytes and monocytes without causing clinical symptoms; however, stressors such as immunosuppressive diseases can reactivate the latent virus. ¹ Our patient, a woman with acute myelogenous leukemia-induced immunosuppression, developed choroiditis in her right eye; mNGS analysis revealed HHV-6B and HHV-7 in the aqueous humor. Untargeted mNGS is particularly useful because it allows detection of numerous potential pathogens within 24 to 48 hours, which can facilitate identification of unexpected organisms. ¹¹

Although HHV-6 is frequently detected in brain tissue, there have been few reports of HHV-6A- and HHV-6B-associated intraocular inflammation.^6–9 To our knowledge, ocular infection involving HHV-7 has not been reported. Sugita et al. described seven patients with uveitis or endophthalmitis who harbored HHV-6, including one patient with HHV-6A infection and six patients with HHV-6B infection. ¹² Moreover, in a study of vitreous fluid samples from 101 patients with intraocular inflammation, ¹³ Cohen and colleagues detected HHV-6A and HHV-6B DNA in approximately 1% of samples; none of those samples contained HHV-7.

Compared with HHV-6A and 7, HHV-6B infection is more commonly reported. ¹ However, HHV-6A is suspected to exhibit greater neurotropism than HHV-6B or 7. In previous reports of intraocular inflammation, HHV-6A infection generally caused meningitis and optic neuritis, with concomitant detection of HHV-6A in cerebrospinal fluid.^7,8 In contrast, HHV-6B-associated intraocular inflammation mainly involved necrotic retinitis or panuveitis. Among the six patients with HHV-6B infection described by Sugita et al., three were diagnosed with uveitis, two were diagnosed with retinitis, and one was diagnosed with corneal endotheliitis. ¹² Most of the six patients also exhibited other viruses (in addition to HHV-6) including herpes simplex virus, cytomegalovirus, and Epstein–Barr virus. Thus, differences in clinical presentation might be related to the presence of different viruses. To our knowledge, this is the first report of HHV-7 involvement in HHV-associated ocular inflammation. In contrast to previous reports, our patient’s ocular inflammation began in the choroid and mainly consisted of choroiditis, which may represent a unique feature of HHV-7 infection.

As noted above, HHV can remain latent in lymphocytes and monocytes; HHV-6 DNA has been detected in circulating leukocytes and monocytes. ⁴ Thus, immune cells may carry HHV-6 and HHV-7 into an inflamed eye. Additionally, a recent study of encephalopathy suggested that HHV-7 has greater affinity for glial and endothelial cells, rather than neurons. ² Similar to the blood–brain barrier, a healthy blood–retina barrier maintains the homeostasis necessary for normal retinal function. The “neuro-glio-vascular unit,” consisting of structured endothelial cells and glial cells, plays an essential role in the integrity of the blood–retina barrier. ¹⁴ Therefore, alterations in the “neuro-glio-vascular unit” might enable the entry of HHV-6 and HHV-7 into ocular tissue.

Conclusions

We have described HHV-6B- and HHV-7-associated choroiditis in an immunosuppressed patient diagnosed with acute myelogenous leukemia. Inflammation substantially improved after treatment with foscarnet and acyclovir. This is the first report of HHV-7 involvement in ocular inflammation. Our findings highlight need to consider HHV-6 and HHV-7 as sources of ocular infection, particularly in immunocompromised patients. Moreover, this report shows that mNGS analysis of ocular fluid is an effective method for the detection of specific pathogens.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231204479 - Supplemental material for HHV-6B- and HHV-7-associated choroiditis secondary to acute myelogenous leukemia: a case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605231204479 for HHV-6B- and HHV-7-associated choroiditis secondary to acute myelogenous leukemia: a case report by Jing Xu, Linjiang Chen, Tao Cen, Yuanping Zeng and Qiong Liu in Journal of International Medical Research