Changes of aqueous cytomegalovirus DNA in patients with cytomegalovirus retinitis after allogeneic bone marrow hematopoietic stem cell transplantation_Chinese Journal of Ocular Fundus Diseases

Authors：

Chen Weibin ¹ , Long Ze ¹ , Hou Jing ¹ , Zhang Zhongchen ² , Zhao Mingwei ¹ ,  Miao Heng ¹

1. Department of Ophthalmology & Clinical center of Optometry, Peking University People's Hospital, Eye Diseases and Optometry Institute, Beijing Key Laboratory Diagnosis and Therapy of Retina and Choroid Diseases, College of Optometry, Peking University Health Science Center, Beijing 100044, China;
2. Department of Ophthalmology, Hebei Yanda Hospital, Sanhe 065201, China;

Corresponding author：

Miao Heng, Email: sawyer_young@sina.com

Keywords：

Cytomegalovirus retinitis; Hematopoietic stem cell transplantation; Aqueous humor; Viral load

DOI：

10.3760/cma.j.cn511434-20211216-00703

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Objective To observe aqueous cytomegalovirus (CMV) DNA load in patients with cytomegalovirus retinitis (CMVR) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and to explore influencing factors for transient elevation of CMV-DNA load during the treatment. Methods A retrospective study. From January 2016 to July 2020, 28 eyes of 19 patients with CMVR after Allo-HSCT diagnosed in the Department of Ophthalmology of Peking University People's Hospital were included in the study. Among them, there were 8 males with 12 eyes, 11 females with 16 eyes; the mean age was 28 years; 10 patients were unilateral and 9 patients were bilateral. During the course of treatment and follow-up, the blood CMV-DNA remained negative. All patients were treated with intravitreal injection of 60 mg/ml ganciclovir 0.05 ml (containing ganciclovir 3 mg), twice a week for two weeks in induction phase and weekly injection in maintenance phase. Aqueous humor sample was collected during injection of ganciclovir (IVG) and CMV-DNA load was determined by real-time quantitative polymerase chain reaction. Intravitreal treatment was terminated if aqueous CMV-DNA load turned negative after the fourth or later intravitreal injection. The patients were followed up every 2 weeks for at least 6 months. Serum CMV-DNA was negative in all patients during treatment and follow-up. All the eyes were divided into continuous decline group and non-continuous decline group depending on whether there was transient elevation of aqueous CMV-DNA load, and data between two groups were compared. Pearson linear regression analysis was used to analyze the correlation between aqueous CMV-DNA load and injection times or treatment duration. Results At the end of treatment, the median number of IVG in the affected eye was 7 (4, 9). The results of correlation analysis showed that the aqueous humor CMV-DNA load of the affected eye was related to the number of treatments [R²=0.385, P＜0.000 1, B=－0.237 log₁₀ copies/(ml · time)], and the duration of treatment [R²=0.394, P <0.000 1, B=－0.301 log₁₀ copies/(ml · week)] were negatively correlated. Among the 28 eyes, 13 eyes (46.4%, 13/28) in the continuous decline group and 15 eyes (53.6%, 15/28) in the non-sustained decline group. Baseline visual acuity (t=－1.223), intraocular pressure (t=1.538), aqueous humor CMV-DNA load (t=－0.109), retinitis lesion area (Z=－0.308) in the continuous decline group and the non-continuous decline group), the number of quadrants involved (Z=－0.024) and whether the macula was involved (Z=－1.826), combined with anterior segment inflammation (Z =－0.499), combined with high intraocular pressure (Z=－1.342), terminal visual acuity (t =－0.845), intraocular pressure (t=－0.068), total IVG times (Z=0.907), age (Z=－0.832), gender composition (Z=－1.074), etc. The difference was not statistically significant (P＞0.05). Conclusion The CMV-DNA load in aqueous humor decreases by about 50% every week during the treatment of CMVR eyes after Allo-HSCT; the transient increase in the CMV-DNA load in the aqueous humor during treatment does not affect the treatment process and clinical prognosis.

Citation： Chen Weibin, Long Ze, Hou Jing, Zhang Zhongchen, Zhao Mingwei, Miao Heng. Changes of aqueous cytomegalovirus DNA in patients with cytomegalovirus retinitis after allogeneic bone marrow hematopoietic stem cell transplantation. Chinese Journal of Ocular Fundus Diseases, 2022, 38(5): 346-352. doi: 10.3760/cma.j.cn511434-20211216-00703 Copy

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7.	Smith IL, Macdonald JC, Freeman WR, et al. Cytomegalovirus (CMV) retinitis activity is accurately reflected by the presence and level of CMV DNA in aqueous humor and vitreous[J]. J Infect Dis, 1999, 179(5): 1249-1253. DOI: 10.1086/314710.
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9.	Humar A, Kumar D, Boivin G, et al. Cytomegalovirus (CMV) virus load kinetics to predict recurrent disease in solid-organ transplant patients with CMV disease[J]. J Infect Dis, 2002, 186(6): 829-833. DOI: 10.1086/342601.
10.	Miao H, Tao Y, Jiang YR, et al. Multiple intravitreal injections of ganciclovir for cytomegalovirus retinitis after stem-cell transplantation[J]. Graefe's Arch Clin Exp Ophthalmol, 2013, 251(7): 1829-1833. DOI: 10.1007/s00417-013-2368-6.
11.	Jeon S, Lee WK. Cytomegalovirus retinitis in a human immunodeficiency virus-negative cohort: long-term management and complications[J]. Ocul Immunol Inflamm, 2015, 23(5): 392-399. DOI: 10.3109/09273948.2014.985385.
12.	Zhang C, Wang YE, Miao H, et al. Efficacy and safety of aqueous interleukin-8-guided treatment in cytomegalovirus retinitis after bone marrow hematopoietic stem cell transplantation[J]. Ocul Immunol Inflamm, 2020, 16: 1-8. DOI: 10.1080/09273948.2020.1823422.
13.	余盈盈, 赵明威, 苗恒. 基于房水病毒学和炎性细胞因子检测的巨细胞病毒性视网膜炎治疗模式的初步研究[J]. 中华眼底病杂志, 2020, 36(1): 1-4. DOI: 10.3760/cma.j.issn.1005-1015.2020.01.001.Yu YY, Zhao MW, Miao H. Regime for cytomegalovirus retinitis based on aqueous virology and inflammatory cytokine determination[J]. Chin J Ocul Fundus Dis, 2020, 36(1): 1-4. DOI: 10.3760/cma.j.issn.1005-1015.2020.01.001.
14.	Boeckh M, Gooley TA, Myerson D, et al. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study[J]. Blood, 1996, 88(10): 4063-4071. DOI: 10.1182/blood.V88.10.4063.bloodjournal88104063.
15.	Gerna G, Zavattoni M, Percivalle E, et al. Rising levels of human cytomegalovirus (HCMV) antigenemia during initial antiviral treatment of solid-organ transplant recipients with primary HCMV infection[J]. J Clin Microbiol, 1998, 36(4): 1113-1116. DOI: 10.1128/Jcm.36.4.1113-1116.1998.
16.	Nichols WG, Corey L, Gooley T, et al. Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes[J]. Blood, 2001, 97(4): 867-874. DOI: 10.1182/blood.v97.4.867.

1. Vadlapudi AD, Vadlapatla RK, Mitra AK. Current and emerging antivirals for the treatment of cytomegalovirus (CMV) retinitis: an update on recent patents[J]. Recent Pat Antiinfect Drug Discov, 2012, 7(1): 8-18. DOI: 10.2174/157489112799829765.
2. Zuhair M, Smit GSA, Wallis G, et al. Estimation of the worldwide seroprevalence of cytomegalovirus: a systematic review and meta-analysis[J/OL]. Rev Med Virol, 2019, 29(3): e2034[2019-01-31]. https://pubmed.ncbi.nlm.nih.gov/30706584/. DOI: 10.1002/rmv.2034.
3. Munro M, Yadavalli T, Fonteh C, et al. Cytomegalovirus retinitis in HIV and non-HIV Individuals[J]. Microorganisms, 2020, 8(1): 55. DOI: 10.3390/microorganisms8010055.
4. Pearce WA, Yeh S, Fine HF. Management of cytomegalovirus retinitis in HIV and non-HIV patients[J]. Ophthalmic Surg Lasers Imaging Retina, 2016, 47(2): 103-107. DOI: 10.3928/23258160-20160126-01.
5. Shapira Y, Mimouni M, Vishnevskia-Dai V. Cytomegalovirus retinitis in HIV-negative patients - associated conditions, clinical presentation, diagnostic methods and treatment strategy[J/OL]. Acta Ophthalmol, 2018, 96(7): e761-e767[2017-10-25]. https://pubmed.ncbi.nlm.nih.gov/29068151/. DOI: 10.1111/aos.13553.
6. Choopong P, Vivittaworn K, Konlakij D, et al. Treatment outcomes of reduced-dose intravitreal ganciclovir for cytomegalovirus retinitis[J/OL]. BMC Infect Dis, 2016, 16: 16164[2016-04-18]. https://pubmed.ncbi.nlm.nih.gov/27090644/. DOI: 10.1186/s12879-016-1490-6.
7. Smith IL, Macdonald JC, Freeman WR, et al. Cytomegalovirus (CMV) retinitis activity is accurately reflected by the presence and level of CMV DNA in aqueous humor and vitreous[J]. J Infect Dis, 1999, 179(5): 1249-1253. DOI: 10.1086/314710.
8. Qian Z, Chen X, Tao Y, et al. Prognostic factors of cytomegalovirus infection associated retinitis in HIV-negative patients: a retrospective cohort study[J]. Ocul Immunol Inflamm, 2021, 29(1): 154-159. DOI: 10.1080/09273948.2019.1659978.
9. Humar A, Kumar D, Boivin G, et al. Cytomegalovirus (CMV) virus load kinetics to predict recurrent disease in solid-organ transplant patients with CMV disease[J]. J Infect Dis, 2002, 186(6): 829-833. DOI: 10.1086/342601.
10. Miao H, Tao Y, Jiang YR, et al. Multiple intravitreal injections of ganciclovir for cytomegalovirus retinitis after stem-cell transplantation[J]. Graefe's Arch Clin Exp Ophthalmol, 2013, 251(7): 1829-1833. DOI: 10.1007/s00417-013-2368-6.
11. Jeon S, Lee WK. Cytomegalovirus retinitis in a human immunodeficiency virus-negative cohort: long-term management and complications[J]. Ocul Immunol Inflamm, 2015, 23(5): 392-399. DOI: 10.3109/09273948.2014.985385.
12. Zhang C, Wang YE, Miao H, et al. Efficacy and safety of aqueous interleukin-8-guided treatment in cytomegalovirus retinitis after bone marrow hematopoietic stem cell transplantation[J]. Ocul Immunol Inflamm, 2020, 16: 1-8. DOI: 10.1080/09273948.2020.1823422.
13. 余盈盈, 赵明威, 苗恒. 基于房水病毒学和炎性细胞因子检测的巨细胞病毒性视网膜炎治疗模式的初步研究[J]. 中华眼底病杂志, 2020, 36(1): 1-4. DOI: 10.3760/cma.j.issn.1005-1015.2020.01.001.Yu YY, Zhao MW, Miao H. Regime for cytomegalovirus retinitis based on aqueous virology and inflammatory cytokine determination[J]. Chin J Ocul Fundus Dis, 2020, 36(1): 1-4. DOI: 10.3760/cma.j.issn.1005-1015.2020.01.001.
14. Boeckh M, Gooley TA, Myerson D, et al. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study[J]. Blood, 1996, 88(10): 4063-4071. DOI: 10.1182/blood.V88.10.4063.bloodjournal88104063.
15. Gerna G, Zavattoni M, Percivalle E, et al. Rising levels of human cytomegalovirus (HCMV) antigenemia during initial antiviral treatment of solid-organ transplant recipients with primary HCMV infection[J]. J Clin Microbiol, 1998, 36(4): 1113-1116. DOI: 10.1128/Jcm.36.4.1113-1116.1998.
16. Nichols WG, Corey L, Gooley T, et al. Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes[J]. Blood, 2001, 97(4): 867-874. DOI: 10.1182/blood.v97.4.867.

Chinese Journal of Ocular Fundus Diseases

Changes of aqueous cytomegalovirus DNA in patients with cytomegalovirus retinitis after allogeneic bone marrow hematopoietic stem cell transplantation

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