• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.25 no.1
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• pp.70-78
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• 2022

Purpose: Cholestasis resulting from cytomegalovirus (CMV)-induced hepatitis manifests in 40% of patients with a CMV infection. Ganciclovir treatment in children with CMV infections has proven to be highly effective. Until now, there are very few studies have identified predictive factors for liver biochemistry improvement after ganciclovir therapy. This study aimed to identify the predictors of liver biochemistry improvement in patients with CMV cholestasis after ganciclovir treatment. Methods: A retrospective cohort study was conducted using medical records from Dr. Sardjito General Hospital Yogyakarta, Indonesia from 2013 to 2018. CMV cholestasis was confirmed based on serum CMV IgG and IgM positivity and/or blood and urine CMV antigenemia positivity. Incomplete medical records and other etiologies for cholestasis, such as biliary atresia, choledochal cyst, metabolic diseases, and Alagille syndrome, were excluded. Patient age at cholestasis diagnosis and ganciclovir treatment, duration of CMV cholestasis, history of prematurity, central nervous system involvement, and nutritional status were analyzed and presented as an odds ratio (OR) with a 95% confidence interval (95% CI). Results: CMV cholestasis with ganciclovir therapy was found in 41 of 54 patients. Multivariate analysis showed that a shorter duration of CMV cholestasis (OR: 4.6, 95% CI: 1.00-21.07, p=0.04) was statistically significant for liver biochemistry improvement after 1 month of ganciclovir treatment. The remaining factors that were analyzed were not significant predictors of liver biochemistry improvement in patients with CMV cholestasis after ganciclovir treatment. Conclusion: A shorter duration of CMV cholestasis is the predictor of liver biochemistry improvement after 1 month gancyclovir treatment.

• Clinical and Experimental Pediatrics
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• v.55 no.12
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• pp.491-493
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• 2012

Cytomegalovirus (CMV)-associated esophageal ulcer is rare in immunocompetent infants. The presence of inclusion bodies and immunohistochemical staining for CMV in biopsy specimens obtained during esophagogastroduodenoscopy (EGD) indicate that such ulcers occur because of CMV infection. A 7-week-old female infant who experienced frequent vomiting and feeding intolerance was diagnosed with a massive CMV-associated ulcer in the distal esophagus. The ulcer improved after conservative treatment using proton-pump inhibitors; however, ganciclovir was not administered. In a follow-up EGD biopsy specimen, no CMV inclusion bodies were present, and immunohistochemical staining results for this virus were negative. The presence of CMV inclusion bodies indicates active viral replication. If persistent inclusion bodies or positive immunohistochemical staining for CMV is observed in follow-up biopsy specimens, ganciclovir may be used to treat CMV-associated esophageal ulcers.

• Journal of Microbiology and Biotechnology
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• v.23 no.8
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• pp.1154-1158
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• 2013

Ganciclovir resistance of human cytomegalovirus is associated with mutations in the viral UL97 gene and poses severe problems for immunocompromised patients. In this study, PCR-based restriction fragment length polymorphism and sequencing analyses detected the UL97 D605E mutation in all five clinical isolates from patients with ganciclovir-resistant human cytomegalovirus infection during prolonged ganciclovir therapy, whereas the M460V mutation was only present in 1 of 5 isolates. On the other hand, the detection rates of the D605E mutation in the stored available DNA samples from the donor and allogeneic stem cell transplantation recipients were 66.7% and 93.7%, respectively, suggesting that the presence of D605E mutation was not associated with the ganciclovir exposure. Although the D605E mutation may not be related to ganciclovir resistance, we suggest that this mutation could be an important molecular marker of human cytomegalovirus evolution in East Asian countries. Moreover, the restriction fragment length polymorphism method using the restriction enzyme HaeIII, which is generally used to detect the UL97 A591V mutation, could also detect the D605E mutation and may therefore be a useful tool for future research on the investigation of UL97 gene mutations.

• Childhood Kidney Diseases
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• v.12 no.2
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• pp.233-238
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• 2008

It has been suspected that various infections, including cytomegalovirus(CMV) infection, are associated with IgA nephropathy. In case of CMV infection, ganciclovir is known to be a treatment of choice for severe CMV infection in general. But ganciclovir has a lot of severe toxicity, so children with normal immunity are seldom treated by ganciclovir when CMV infection is suspected. On the other hand, intravenous immunoglobulin can also be used to treat CMV infection. We report a case of CMV-associated IgA nephrophaty, who was treated with deflazacort and Intravenous immunoglobulin therapy. An 11 years old boy suffered from gross hematuria for 3 days. He had proteinuria, thrombocytopenia(104,000/$mm^3$), antiplatelet antibody(＋), impaired renal function and low serum albumin. His CMV serology was CMV-IgM/IgG(＋/-) and urine CMV-PCR was positive. The renal histological findings revealed IgA nephropathy, WHO class II. His proteinuria persisted despite of deflazacort therapy(2.5 mg/kg/day). Later, intravenous immunoglobulin(1 g/kg) was administered twice. In two years, he showed no gross and microscopic hematuria, and his laboratory findings were also normalized.

• Animal cells and systems
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• v.2 no.2
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• pp.249-258
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• 1998

Obesity, one of the most common metabolic diseases in industrial countries is characterized by an increase in the number or size of adipocytes. In an effort to create transgenic mouse models for the study of obesity we developed a novel technique in which adipose tissue can be ablated genetically at will, at any specific developmental stage and/or physiological condition, by the treatment of ganciclovir. We made a series of adipocytespecific expression vectors using minimal regulatory regions of brown adipocyte-specific uncoupling protein (UCP-1) gene and adipocyte-specific aP2 gene, and then analyzed their expression characteristics in cultured cell lines. When both constructs pUCP-LacZ and paP2-LacZ were transfected transiently into differentiating 3T3-L1 (pre-while adipocytes) and HIB-1B (pre-brown adipocytes) cell lines in vitro and then monitored by X-gal staining of cells, these regulatory regions were sufficient to show proper differentiation stage-specific expression in adipocvtes. To confirm that adipocytes expressing HSV-TK controlled by these minimal requlatory elements are sufficient to kill themselves with ganciclovir treatment pUCP-TK and paP2-TK expression constructs were transfected stably into HIB-1B and 3T3-L1 cells, respectively, and their ganciclovir sensitivities were tested during in vitro differentiation of cells. As expected more than 80% of cells were dead by the 7th day of treatment with ganciclovir while negative control cells were not affected at all. The data suqqest that the constructed vectors are suitable for obtaining novel obese transqenic models based on a conditional genetic tissue ablation method.

• Pediatric Infection and Vaccine
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• v.27 no.3
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• pp.198-204
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• 2020

Cytomegalovirus (CMV) disease is rare in children who receive anticancer chemotherapy and have no history of stem cell transplantation (SCT). We report a case of CMV retinitis that developed during maintenance chemotherapy for acute leukemia. A 7-year-old boy developed decreased visual acuity and persistent pancytopenia during maintenance chemotherapy. Laboratory investigations initially showed significant CMV antigenemia (51 positive cells/200,000 leukocytes); however, antiviral therapy was not deemed necessary in this patient who had no history of SCT. CMV antigenemia worsened to 170 positive cells/200,000 leukocytes over 3 weeks. Ophthalmological examination revealed multiple bilateral retinal infiltrates and granular lesions. He was diagnosed with CMV retinitis and was treated with a 4-week course of intravenous ganciclovir and intravitreal injection of ganciclovir 6 times, followed by a 1-month course of orally administered valganciclovir. A CMV antigenemia assay showed negative results, and follow-up fundoscopy revealed lesser retinal infiltration after the sixth intravitreal ganciclovir injection. Future studies should focus on the development of standardized screening methods and preemptive therapeutic strategies for CMV disease in high-risk children.

• The Journal of Korean Society of Virology
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• v.28 no.4
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• pp.359-368
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• 1998

Cytomegalovirus is the most common cause of life-threatening viral infection in HIV-infected patients. This study was done prospectively to investigate the incidence of CMV infection according to the decrease of CD4+ T cell count (CD4+) in Korean AIDS patients. Thirty-nine HIV-infected patients diagnosed before 1994 were followed for regular immunological monitoring. We have used urine shell vial method for the CMV detection from 1994 and have also checked clinical findings. Positive urine culture rate definitely depended on the CD4+ as follows; 45%, 22%, 17%, 11% and 0%, CD4+ <50, 50-100, 100-200, 200-500 and >500, respectively. Except culture positive 2 patients with CD4+ of $200{\sim}300/{\mu}l$, all eight culture positive patients with CD4+ less than $200/{\mu}l$ showed CMV related diseases on or before urine culture. But, we could not get a positive culture for a late AIDS patient with vision loss. With ganciclovir therapy, all culture results were at least negative just after or on late of first 14 days-ganciclovir infusion-course. These data suggest that the incidence of CMV disease in Korean AIDS patients is very high, and early diagnosis and treatment for CMV diseases is required for the prevention of life threatening results.

• Tuberculosis and Respiratory Diseases
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• v.46 no.2
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• pp.229-240
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• 1999

Background: The impact of the immune response on cancer gene therapy using viral vectors to deliver a "suicide gene" is currently unclear. A vigrous immune response targeted at viral proteins or transgene may enhance the efficacy of tumor destruction and even augment responses to tumor antigens. These responses may involve the release of cytokines and stimulation of tumor specific cytotoxic T-lymphocytes that enhance therapeutic efficacy. On the other hand, a vigorous rapid cellular immune response may destroy cells expressing the therapeutic gene and attenuate the response to therapy. Furthermore, development of neutralizing antibody responses may prevent readministration of virus, a potentially significant limitation. Evaluating the significance of these limitations in animal models and developing solutions are therefore of obvious importance. Methods: After retroviral transduction of mouse mesothelioma cell line(AB12) with Herpes Simplex Virus thymidine kinase (HSVtk) gene in vitro, subcutaneous flank tumors were established. To study the effect of intact immune system on efficacy of tumor erradication, the ability of the HSVtk/ganciclovir system to inhibit tumor growth was compared among normal Balb/c mice, immunodeficient Balb/c-nude and SCID mice, and Balb/c mice immunosuppressed with cyclosporin. Results: Ganciclovir treatment resulted in greater inhibition of tumor growth in Balb/c mice compared with immunodeficient Balb/c-nude mice and SCID mice(in immunodeficient mice, there were no growth inhibition by ganciclovir treatment). Ganciclovir treatment resulted in greater inhibition of tumor growth in noncyclosporin (CSA) treated Balb/c mice compared with CSA treated Balb/c mice. On day 8, mean ganciclovir-treated tumor volume were 65% of control tumor volume in Balb/c mice versus 77% control tumor volume in CSA-treated Balb/c mice. This effect was still evident during therapy (day 11 and 13). On day 13, non-CSA treated tumor volume was 35% of control tumor volume versus 60% of control tumor volume in CSA treated Balb/c mice. Duration of expression of HSVtk was not affected by the immunosuppression with CSA. Conclusion: These results indicate that the immune responses against retrovirally transduced cells enhance the efficacy of the HSVtk/ganciclovir system. These findings have important implications for clinical trials using currently available retrovirus vectors as well as for future vector design.

• Proceedings of the PSK Conference
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• 2000.04a
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• pp.145.3-146
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• 2000

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.15 no.2
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• pp.91-99
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• 2012

Purpose: The aims of this study was to compare and evaluate the clinical characteristics, laboratory data, and prognosis for infants under age 1 year with CMV hepatitis and those with viral hepatitis of unknown etiology. Methods: A retrospective study was conducted of infants under age 1 year who were admitted with acute hepatitis. The exclusion criteria consisted of: autoimmune, genetic, metabolic, toxic, HAV, HBV, HCV, toxoplasma, rubella, herpes simplex, and Epstein-Barr virus. The 30 patients included were divided into two groups based on markers for CMV (IgM anti-CMV, CMV PCR in urine, CMV culture in urine). Results: The median age of patients (n=15) was 2.8 months. No other organ involvement was detected in any patient. Peak serum total bilirubin levels (n=4) ranged from 2.6 to 6.7 mg/dL. Peak serum ALT levels ranged from 51 to 1,581 IU/L. The duration of ALT elevation ranged from 1.5 weeks to 26 weeks (median 9 weeks). All had recovered in full without ganciclovir; there were no cases of hearing loss. The median age of controls (n=15) was 2.5 months. Peak serum total bilirubin levels (n=4) ranged from 1.6 to 9.1 mg/dL. Peak serum ALT levels ranged from 26 to 1,794 IU/L. No significant differences were observed between both groups regarding the peak serum ALT levels, peak serum total bilirubin levels, duration of hyperbilirubinemia and ALT elevation. Conclusion: Although it was not possible to differentiate congenital infection with perinatal infection in this study, the prognosis of patients with CMV hepatitis without other organ involvement was good without ganciclovir treatment.