EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Cytomegalovirus remains the most common infection after kidney transplant. We report cytomegalovirus retinitis and anterior uveitis, which developed consecutively within 1 year in a kidney transplant recipient. A 25-year-old man presented 5 months after transplant with decreased visual acuity in his left eye. Fundus examination revealed bilateral areas of necrotizing retinitis with intraretinal hemorrhages. The confirmation of cytomegalovirus disease was based on clinical findings and positive polymerase chain reaction for cytomegalovirus in plasma and in aqueous humor. The patient was treated with intravenous ganciclovir for 21 days and then with valacyclovir for 3 months. The patient’s symptoms improved, and fundus examination revealed resolution of retinitis with appearance of retinal scarring. One year later, the patient presented with cytomegalovirus anterior uveitis associated with increased intraocular pressure, which was treated with antiviral agents, antiglaucomatous eye drops, and trabeculectomy. Cytomegalovirus ocular involvement for our immunocompromised patient presented in 2 consecutive forms: bilateral retinitis and anterior uveitis. Early diagnosis and treatment of active cytomegalovirus retinitis and uveitis remain crucial to prevent their progression to irreversible visual impairment.

Key words : Infection, Retinitis, Uveitis

Cytomegalovirus (CMV) remains the most common infection after kidney transplant. Patients can develop specific organ CMV disease (eg, encephalitis, colitis, and retinitis) with a significant risk of morbidity and mortality. Cytomegalovirus retinitis can develop and threaten vision in renal transplant patients. Cytomegalovirus infection can also cause anterior segment inflammation. This report details 2 CMV ocular involvements, retinitis and uveitis, in a kidney transplant recipient.

A 25-year-old otherwise healthy male patient, who had developed end-stage renal disease of unknown cause, underwent living-related kidney transplant. Both donor and recipient were seropositive for CMV. He had an immunosuppressive induction therapy based on thymoglobulin and methylprednisolone. The posttransplant course was complicated by lymphocele, which required surgical drainage. After that, the serum creatinine concentration remained stable between 180 and 200 μmol/L on an immunosuppressive regimen that consisted of tacrolimus, mycophenolate mofetil, and prednisone. The patient did not receive CMV prophylaxis.

Five months after transplant, the patient presented with decrease in visual acuity in the left eye concomitant with hacking cough, diarrhea, and fever. Physical examination revealed temperature of 38.5°C, heart rate of 70 beats/min, respiratory rate of 16 breaths/min, and blood pressure of 130/70 mm Hg. Oxygen saturation was 98% on room air. Chest auscultation revealed bilateral fine inspiratory crackles. Cardiac, abdominal, and neurologic examinations were unremarkable.

Initial laboratory investigations revealed leukopenia with white blood cell concentration of 3200/mm³, hemoglobin level of 12.5 g/dL, and platelet count of 132 000/mm³. Liver function tests were within normal limits (aspartate aminotransferase = 18 IU/L, alanine aminotransferase = 24 IU/L, total bilirubin = 1.8 mg/dL).

Chest radiography showed interstitial lung disease. On ophthalmic examination, best corrected visual acuity (BCVA) was 20/20 in the right eye and 20/40 in the left eye. Slit-lamp examination was normal in both eyes, with no signs of anterior uveitis. There were 1+ vitreous cells in both eyes. Fundus examination showed bilateral areas of necrotizing retinitis with intraretinal hemorrhages involving superior and temporal-superior retina in the right eye and posterior pole and temporal-superior retina in the left eye (Figures 1 and 2). Both polymerase chain reaction results in plasma and in aqueous humor were positive for CMV. On the basis of clinical findings and polymerase chain reaction results, the diagnosis of CMV disease was made, involving bilateral CMV retinitis and CMV pneumonitis, and the patient was treated with intravenous ganciclovir (5 mg/kg every 12 h adjusted according to renal function) for 21 days. One week after treatment, the patient’s diarrhea and fever resolved. Intravenous ganciclovir was followed by valacyclovir at a dose of 1500 mg orally 3 times daily for 3 months, with improvement of BCVA to 20/25 in the left eye and healing of necrotizing retinitis in both eyes (Figure 3).

One year later, the patient developed recurrence of CMV disease with fever. Laboratory investigations showed leukopenia (3100 white blood cells/mm3) and liver function test abnormalities (elevated alanine aminotransferase levels). On ophthalmologic examination, BCVA was 20/25 in both eyes. Slit-lamp examination revealed bilateral anterior uveitis with keratic precipitates and 2+ anterior chamber cells. Intraocular pressure was 25 mm Hg in the right eye and 36 mm Hg in the left eye, and there was no retinitis in either eye. Polymerase chain reaction results in the aqueous humor were positive for CMV. The patient was treated with intravenous ganciclovir (5 mg/kg every 12 h) for 21 days, together with antiglaucomatous eye drops. However, despite maximal antiglaucomatous treatment, intraocular pressure remained high in the left eye, and the patient underwent trabeculectomy 2months later. Valacyclovir dose of 1500 mg orally 3 times daily was maintained for 4 months. At the last follow-up (24 months later), the patient had stable graft function with no further recurrence of CMV disease and controlled intraocular pressure.

The incidence of CMV infection after kidney transplant varies between 30% and 75%. In contrast, the incidence of CMV disease is 8% to 35% in kidney, heart, and liver transplant recipients.¹ It occurs mainly during the first 2 months after transplant. Its occurrence may be secondary to a primary infection (transfusion, allograft) or a reactivation (after a lag period in the endothelial system, monocytes).^1,2

In a series of recipients of allogeneic hematopoietic stem cell transplantation, CMV retinitis developed in 4% of patients. This represented 23% of those with significant CMV viremia.³ In the eye, CMV most commonly presents as a viral necrotizing retinitis with a characteristic ophthalmoscopic appearance. Retinitis typically starts in the midperiphery and can progress.^3,4 Most patients with CMV retinitis will initially present with unilateral disease.⁵ Our patient presented with bilateral areas of necrotizing retinitis involving the posterior pole in the left eye.

Cytomegalovirus infection is increasingly recognized as an important cause of anterior segment inflammation. Clinical features of CMV anterior segment inflammation include increased intraocular pressure and anterior chamber inflammation.⁶ High intraocular pressure can occur in patients with CMV-related corneal endotheliitis; its occurrence may be related to inflammation of the trabecular meshwork.^6,7 Our patient developed increased intraocular pressure that required trabeculectomy.Although tissue samples can confirm CMV infection by laboratory testing, clinical appearance of retinitis is often used for diagnosis. Untreated CMV retinitis inexorably progresses to visual impairment and blindness.^3,4The prevalence varies considerably with serologic status of donor-recipient couple. Risk factors of CMV infection are donor positive/recipient negative CMV status, T-cell-depleting antibody therapy, and treatment of acute rejection with high doses of steroids.⁸

Both prophylactic and preemptive strategies exist to prevent the development of clinical disease.^8,9 Prophylactic treatment is necessary in high-risk populations as an early treatment. Prophylactic treatment is given to all high-risk groups. It is logistically easy and efficacious, but increased exposure can lead to drug toxicity and can cause resistance. It is safer for high-risk patients with seronegative recipients and those treated with T-cell-depleting antibody therapy. In fact, prophylaxis can reduce CMV infection, disease, and mortality.^8,10 In our country, resources limit the use of oral valganciclovir for prophylaxis for CMV-seropositive patients.

Preemptive therapy includes frequent monitoring of viral load and treating only when the threshold is achieved. The advantages of this strategy is to reduce drug exposure and toxicity and to lower risk of resistance and reduce late-onset disease (by allowing cell-mediated immunity); however, this can be logistically difficult, especially in our center because of the high cost of panel reactive tests for monitoring viral load.⁹

Guidelines exist regarding the optimal treatment of CMV infection, but, because all methods have benefits and risks, individual transplant centers must decide on the most appropriate method. It is important to weigh the strategy against the incidence of CMV in a particular center.¹⁰ Valganciclovir and intravenous ganciclovir are generally the first-line agents used to treat CMV infection. In patients with severe or life-threatening CMV disease, intravenous ganciclovir remains the preferred drug.¹¹

Cytomegalovirus disease frequently recurs after treatment. The use of secondary prophylaxis for 1 to 3 months after treatment varies considerably across transplant centers but is frequently employed, especially when the risk of relapse is high.¹² Our patient had received valacyclovir for 3 months after CMV retinitis but presented recurrence of CMV infection.

Reduction of immunosuppression should be strongly considered in patients with severe CMV disease, those with very high viral loads, and those with clinically refractory disease. The role of CMV immunoglobulin in the treatment of CMV disease is unclear, but it is sometimes used as adjunctive therapy in patients with severe forms of CMV disease.^10,11

In patients undergoing allogenic hematopoietic stem cell transplant after conditioning with an alemtuzumab (Campath, Genzyme, Cambridge, MA, USA)-based regimen, the frequency of CMV retinitis can approach 24%. Regular screening for retinitis in this population is also warranted.¹³ The latest data from the Longitudinal Study of Ocular Complications of Acquired Immunodeficiency Syndrome have indicated that patients treated with intravitreal therapy alone, compared with those treated with systemic regimens (with or without intravitreal therapy) or with ganciclovir, may have worse ocular outcomes, in terms of final visual acuity, progression of retinitis, and loss of visual field, even after adjusting for known confounders.^14,15

Important progress has been made with diagnosis, prevention, and treatment of CMV disease. Early diagnosis and treatment of active CMV retinitis and uveitis remain crucial to obtaining the best visual prognosis in affected individuals.

Volume: 16 Issue: 4 August 2018

FULL TEXT