Floaters Affect Vision of Kidney Transplant Patient

A kidney transplant recipient in their mid-30s developed new-onset floaters in both eyes, according to a case report in JAMA Ophthalmology.

The patient had received a kidney from a deceased donor. Medical history also included cytomegalovirus (CMV) colitis and CMV viremia and documented UL97 and UL54 gene mutations, reported Lauren A. Dalvin, MD, and colleagues at Mayo Clinic in Rochester, Minnesota.

The patient's CMV viremia had previously demonstrated resistance to foscarnet and ganciclovir. Systemic immunosuppressive treatment with maribavir had been discontinued recently in response to resistance concerns, and cidofovir and CMV immune globulin had been gradually introduced.

Clinical examination revealed visual acuity of 20/25 OD and 20/20 OS. Findings on motility, visual fields, and anterior segment assessment were normal. A dilated fundus examination showed "tortuous vasculature, multiple cotton wool spots along the arcades and periphery, and granular, hypopigmented retinal lesions without hemorrhage in the macula and temporal periphery in both eyes," the case authors said.

Optical coherence tomography revealed localized areas of full-thickness retinitis. Serology showed CMV titers of 2.24 million IU/mL, indicating viremia. Despite the patient's known UL97 and UL54 mutations, a series of five intravitreal injections of foscarnet and ganciclovir were administered on a biweekly basis in an effort to address the vision-threatening lesions.

The intravitreal treatment did not improve the patient's retinal pathology; in fact, each injection was followed by pain and temporarily reduced visual acuity. This ultimately led to the patient's refusing further intravitreal therapy.

Dalvin and colleagues diagnosed the patient with UL97- and UL54-resistant CMV retinitis.

The team considered various next steps. Continuing treatment with systemic cidofovir and CMV immune globulin or with intravitreal injections of foscarnet and ganciclovir were both quickly dismissed as suboptimal. The patient had found the transient adverse effects of the latter intolerable, they explained. Additionally, "no significant improvement was seen using these medications in the context of documented mutations in the UL97 and UL54 genes."

A UL97 gene mutation contributes to ganciclovir and valganciclovir resistance, and a UL54 gene mutation is associated with resistance to ganciclovir, valganciclovir, foscarnet, and cidofovir, Dalvin and colleagues said. Given the patient's high viral load, benefits of leflunomide would also be short-lived, they noted, since resistance would probably develop soon after treatment was initiated.

The team pointed to cytotoxic T lymphocytes (CTLs) as a novel therapy for CMV retinitis that is not responding to standard therapies. "A type of immunotherapy, CTLs involve adoptive transfer of donor T cells to provide a virus-specific immune response to clear infection," they explained.

In this case, treatment with the multivirus-specific T-cell therapy posoleucel resulted in dramatic improvements within 1 month of the first infusion. Positive response was observed in retinal outcomes as well as in CMV titers, which decreased from 2.24 million IU/mL to 14,700 IU/mL. The patient's active retinitis resolved completely, with residual scarring, and visual acuity was maintained at 20/20 OD and 20/25 OS.

Eight weeks after the patient's initial diagnosis -- 6 weeks after the first infusion -- the patient returned for a follow-up assessment. At that point, some vision loss had occurred. The patient's best-corrected visual acuity was 20/70 OD and 20/60 OS.

On follow-up examination with optical coherence tomography, the team noted new subretinal fluid under the fovea in both eyes, and a bilateral increase in retinal thickness (right eye: 273 to 336 μm; left eye: 273 to 324 μm). "CMV lesions in both eyes remained inactive," Dalvin and co-authors said.

Before the team was able to perform further testing, the patient developed posttransplant lymphoproliferative disorder, which caused a rapid deterioration in health status. The patient was transitioned to hospice care.

"The patient's decreased vision could represent an adverse effect of CTL therapy or cidofovir, but the critically ill status of the patient precluded definitive diagnosis," Dalvin's group said.

Discussion

CMV retinitis that develops in patients following an organ transplant can be challenging to treat due to the need for long-term immunosuppression, which authors noted must be accompanied by "ongoing antiviral therapy for an increasingly resistant virus."

Literature is sparse regarding outcomes of CMV retinitis that has been treated with CTL therapy, Dalvin and colleagues observed. They cited one report of use of CMV-specific T-cell treatment in a series of seven patients "in which 90% of eyes achieved disease resolution and 80% had stable or improved visual acuity."

Before receiving CTL therapy, progressive retinitis persisted in all patients despite their receiving systemic and intravitreal antiviral therapy. Of the seven patients, three had UL97 mutations and one had a UL54 mutation, the authors noted. "Underlying immunosuppression was secondary to stem cell transplant in four patients, AIDS in two patients, and kidney transplant in one patient."

In that small number of patients, treatment was well tolerated. None were affected by immune recovery uveitis; there was one case of cystoid macular edema, and two cases of retinal detachment.

Beyond ocular complications, CTL therapy can be associated with adverse systemic effects, according to studies in oncology patients, which have described cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and cytopenias.

However, in contrast to the seven-patient series described above, "we used multivirus-specific T-cell therapy rather than CMV-specific T cells," Dalvin and team said. "Overall, CTL therapy is a promising novel therapy that requires further investigation, ideally with prospective trials, to evaluate its role in the treatment for CMV retinitis."

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