Therapeutic drug monitoring of ganciclovir for postnatal cytomegalovirus infection in an extremely low birth weight infant: a case report.

BACKGROUND: Ganciclovir is a therapeutic choice for extremely premature infants with severe postnatal cytomegalovirus disease, but little is known about its optimal dose size and dosing interval for them. CASE PRESENTATION: We treated an extremely premature female infant with postnatal cytomegalovirus infection with intravenous administration of ganciclovir since 49 days of life (postmenstrual age of 31 weeks). After ganciclovir treatment was initiated at a dose of 5 mg/kg every 12 h, cytomegalovirus loads in the peripheral blood were markedly decreased. However, since plasma ganciclovir trough level was too high, the interval was extended to every 24 h. Subsequently, the trough level and the estimated 12-h area under the concentration-time curve (AUC0-12) were decreased from 3.5 mg/L to 0.3 mg/L and 53.9 mg · h/L to 19.2 mg · h/L, respectively, resulting in an exacerbation of viremia and clinical condition. Adjustment of dosing interval from 24 h to 12 h led to a peak level of 4.2 mg/L, trough level of 1.1 mg/L, and AUC0-12 of 31.8 mg · h/L, resulting in a marked suppression of viral load. CONCLUSIONS: Monitoring the therapeutic drug levels and cytomegalovirus loads is useful in obtaining a proper treatment effect and preventing overdosage during ganciclovir therapy in premature infants with postnatal cytomegalovirus infection.

Possible vertical transmission of Chikungunya virus infection detected in the cord blood samples from a birth cohort in Vietnam.

BACKGROUND: Chikungunya virus (CHIKV) is an alphavirus (genus Alphavirus, family Togaviridae) that is primarily transmitted to humans by Aedes mosquitoes, and can be transmitted from mother to child. Little is known about CHIKV transmission in Vietnam, where dengue is endemic and Aedes mosquitoes are abundant. This study aimed to determine the prevalence and characteristics of vertical CHIKV infection in a birth cohort, and seroprevalence of anti-CHIKV antibodies with or without confirmation by neutralization tests among women bearing children in Vietnam. METHODS: We collected umbilical cord blood plasma samples from each newly delivered baby in Nha Trang, Central Vietnam, between July 2017 and September 2018. Samples were subjected to molecular assay (quantitative real-time RT-PCR) and serological tests (anti-CHIKV IgM capture and IgG indirect enzyme-linked immunosorbent assay, and neutralization tests). RESULTS: Of the 2012 tested cord blood samples from newly delivered babies, the CHIKV viral genome was detected in 6 (0.3%) samples by RT-PCR, whereas, 15 samples (0.7%) were anti-CHIKV-IgM positive. Overall, 18 (0.9%, 95% CI: 0.6-1.5) samples, including three positives for both CHIKV IgM and viral genome on RT-PCR, were regarded as vertical transmission of CHIKV infection. Of the 2012 cord blood samples, 10 (0.5%, 95% CI: 0.2-0.9) were positive for both anti-CHIKV IgM and IgG. Twenty-nine (1.4%, 95% CI: 1.0-2.1) were seropositive for anti-CHIKV IgG while 26 (1.3%, 95% CI: 0.8-1.9) of them were also positive for neutralizing antibodies, and regarded as seropositive with neutralization against CHIKV infection. CONCLUSION: This is the first report of a possible CHIKV maternal-neonatal infection in a birth cohort in Vietnam. The findings indicate that follow-up and a differential diagnosis of CHIKV infection in pregnant women are needed to clarify the potential for CHIKV vertical transmission and its impact in the newborn.

[Adverse drug reactions of antiviral agents].

Principally speaking, "drug" and "poison" are of the same class; therefore, overdose of any drug naturally leads to intoxication. Intoxication can also occur in regular doses, depending on the condition of a patient (e.g., renal insufficiency). In addition, each drug has its own side effects which occur at a certain probability, and there is no exception to antivirals. Antivirals for common acute viral diseases are used for a number of people, and those for chronic viral diseases are used for a long period. In both cases, side effects are an extremely important issue. Without precise and prompt safety measures, we won't succeed in antiviral treatment.

Rubella seroprevalence among mothers and incidence of congenital rubella three years after rubella vaccine introduction in Vietnam.

Following a rubella outbreak in 2011, Vietnam implemented a mass measles-rubella vaccination campaign for children aged 1-14 years in 2014-2015, further expanding the target age to 16-17 years in 2016; routine vaccination was introduced in 2014. However, there was concern that a substantial proportion of women of child-bearing age were still susceptible to rubella, with the fear of congenital rubella emergence. Thus, we conducted a prospective cohort study in Nha Trang, Vietnam, from 2017-2018 to investigate pregnant women's susceptibility to rubella infection, the incidence of congenital rubella infection, and factors associated with susceptibility. Cord blood was tested for rubella-specific immunoglobulin M (IgM) and IgG; neonatal saliva and cord blood specimens were examined for rubella-RNA. We analyzed 2013 mother-baby pairs. No baby was rubella-IgM or rubella-RNA positive. Overall, 20.4% of mothers were seronegative (95% confidence interval, 18.6%-22.1%). The seronegativity was significantly low among mothers aged <35 years. We found that maternal age groups of 20-24 and 25-29 years, and the lack of self-reported vaccination history were significantly associated with seronegativity. Many pregnant women who were not covered by the vaccination campaign are still at risk of rubella infection.

Congenital Zika Virus Infection in a Birth Cohort in Vietnam, 2017-2018.

To detect congenital ZIKV infection (CZI) in a birth cohort and among high-risk neonates in Vietnam, we collected umbilical cord blood plasma samples of newly delivered babies and peripheral plasma samples of high-risk neonates in Nha Trang, central Vietnam, between July 2017 and September 2018. Samples were subjected to serological and molecular tests. Of the 2013 newly delivered babies, 21 (1%) were positive for Zika virus (ZIKV) IgM and 1,599 (79%) for Flavivirus IgG. Among the 21 ZIKV IgM-positives, 11 were confirmed to have CZI because their plasma samples had anti-ZIKV neutralization titers ≥ 4 times higher than those against dengue virus (DENV)-1 to 4 and Japanese encephalitis virus (JEV) and were tested for the ZIKV RNA positive by real-time reverse transcription-PCR. Therefore, the incidence of CZI in our birth cohort was approximately 0.5%. Of the 150 high-risk neonates, three (2%) and 95 (63%) were positive for ZIKV IgM and Flavivirus IgG antibodies, respectively. None of the three ZIKV IgM-positives had ≥ 4 times higher anti-ZIKV neutralization titers than those against DENV-1 to 4 and JEV, and were therefore considered as probable CZI. Our results indicate that CZI is not rare in Vietnam. Although those with confirmed CZI did not show apparent symptoms suspected of congenital Zika syndrome at birth, detailed examinations and follow-up studies are needed to clarify the CZI impact in Vietnam. This is the first report of CZI cases in a birth cohort in Asia.

Retrospective diagnosis of congenital cytomegalovirus infection at a school for the deaf by using preserved dried umbilical cord.

A retrospective diagnosis of congenital cytomegalovirus infection was made for 3 of 26 students (12%) with either bilateral profound or severe sensorineural hearing loss at a School for the Deaf in Japan by detecting viral DNA with real-time polymerase chain reaction from dried umbilical cords that had been preserved at home.

Central nervous system post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: The Nagasaki transplant group experience.

A 17-year-old male received allogeneic transplantation for acute lymphoblastic leukemia, and presented with generalized seizures due to a solitary brain lesion with massive necrosis on day +621. Epstein-Barr virus (EBV) DNA copies were below the cut-off value in plasma. Stereotactic biopsy of the cerebral lesion confirmed the diagnosis of post-transplant lymphoproliferative disorder (PTLD) with large atypical cells positive for CD20 and EBER. In order to diagnose primary central nervous system PTLD, the biopsy should be applied as early as possible when brain lesion with necrosis develops in post-transplant patients regardless of EBV-DNA in plasma.

Human T-cell leukemia virus type I-associated myelopathy following living-donor liver transplantation.

This report describes a patient who developed human T-cell leukemia virus type I-associated myelopathy (HAM) following a living-donor liver transplantation (LDLT) for liver cirrhosis due to hepatitis C virus (HCV) infection. Both the recipient and the living donor (his sister) were human T-cell leukemia virus type I (HTLV-I) carriers. Since the LDLT, he had been treated with immunosuppressive drugs such as tacrolimus and steroids as well as interferon-alpha to prevent rejection and a recurrence of the HCV infection, respectively. Even though the HTLV-I proviral load had decreased upon interferon treatment, he developed a slowly progressive gait disturbance with urinary disturbance 2 years after the LDLT and was diagnosed with HAM. This appears to be the first report of HAM development in an HLTV-I-infected LDLT recipient.

No association of mouse mammary tumor virus-related retrovirus with Japanese cases of breast cancer.

Mouse mammary tumor virus (MMTV) is the causative agent of breast tumors in mice. Recently, DNA sequences homologous or closely related to MMTV env gene have been specifically detected in breast cancer tissue from significant numbers of American, Australian, and Tunisian women, suggesting a viral etiology for at least a part of human breast cancer. However, the viral sequences have not been detected from any of breast cancer samples in several subsequent studies. Thus, whether MMTV-related retrovirus is a causative agent of human breast cancer remains controversial. To demonstrate if MMTV-related retrovirus is involved in Japanese cases of breast cancer, breast tissue specimens from 46 breast cancer patients and 3 patients with benign mammary tumors were investigated. Extensive analysis using PCR and Southern blot hybridization, however, could not detect the MMTV env gene-like sequence in any of the samples tested as well as in MCF7 cells that has previously been described as a positive control. Thus, MMTV itself or MMTV-related retrovirus is not associated with breast carcinogenesis in Japanese women, and it is unclear whether this conclusion is merely a reflection of regional differences in its epidemics.

TT virus prevalence, viral loads and genotypic variability in saliva from healthy Japanese children.

AIM: TT virus (TTV) is genetically variable and widespread without apparent pathogenicity; however, its epidemiological features in children were not fully understood, partly because blood sampling is often unacceptable for healthy children. We therefore used saliva specimens to investigate epidemiology of TTV infection in early childhood. METHODS: Saliva samples were collected from 83 1-month-old, 110 4-month-old and 49 42-month-old children. Peripheral blood mononuclear cells (PBMC) and saliva samples were obtained in pairs from 19 healthy adults aged 40 +/- 7 years. TTV DNA was detected and quantified by real-time PCR and classified into five genogroups (G1-G5) by a series of PCRs using genogroup-specific primer pairs. RESULTS: TTV DNA was detected in 6, 34 and 90% of children aged 1, 4 and 42 months, respectively, and in 84% of adults. Comparable levels of TTV DNA were detected in pairs of saliva and PBMC. TTV loads in saliva were much higher in children than in adults. G3 was the most common genogroup in all age groups. The second most prevalent was G4 at 1-4 months of age and G1 thereafter. CONCLUSION: The prevalence of TTV infection reached a plateau at or before 42 months; however, somehow different epidemiologic features were observed among genogroups.

Retrospective diagnosis of congenital cytomegalovirus infection using umbilical cord.

Approximately 90% of infants congenitally infected with cytomegalovirus are asymptomatic at birth, but a number of them later develop central nervous system disorders. However, diagnosis of congenital infection with virologic or serologic evidence had been almost impossible beyond the neonatal period. Recently, dried blood spots on Guthrie cards have been demonstrated to be useful for retrospective diagnosis of congenital cytomegalovirus infection; however, they are usually stored for only 1 year. In Japan, the umbilical cord is kept clean and dry as a symbol of the mother-to-child bond, and in recent studies, cytomegalovirus deoxyribonucleic acid was successfully detected from dried umbilical cord of two 1-year-old children who were clinically suspected of having had congenital cytomegalovirus infection. This report describes a 4-year-old male with various central nervous system disorders who was diagnosed with congenital cytomegalovirus infection by detecting cytomegalovirus deoxyribonucleic acid from dried umbilical cord.

Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit.

AIM: Congenital cytomegalovirus (CMV) infection can cause a variety of neurological deficits of delayed onset in infants who are asymptomatic at birth. The aim of this study was to investigate the prevalence of congenital CMV infection among children with autism spectrum disorder (ASD) in Nagasaki, Japan. METHODS: Twenty-nine children with ASD who were born in Nagasaki and had no other major neurological deficits were recruited. Two of the patients were excluded due to significant perinatal events. The remaining 27 children were investigated retrospectively for congenital CMV infection by analyzing dried blood spot samples or dried umbilical cords for CMV DNA using real-time PCR. RESULTS: CMV DNA was detected in two (7.4%) of the 27 children. Neither of the patients had perinatal histories suggestive of congenital CMV disease or other neurological deficits, including hearing impairment and epilepsy. The severity of their autistic disorders varied considerably. CONCLUSIONS: The rate of congenital CMV infection in this study (two of 27 children with ASD), which was significantly (p=0.004) higher than the incidence of congenital CMV infection in Nagasaki (0.31%, 10/3230 live births), suggests the involvement of congenital CMV infection in a portion of children with ASD, although definite diagnosis was not obtained due to limited clinical data of the study subjects.

Persistent hepatitis associated with chronic active Epstein-Barr virus infection.

A previously healthy boy developed persistent hepatitis without fever or lymphoproliferative disorder. Although serologic tests were not indicative, Epstein-Barr virus (EBV) genome and transcripts were detected from the liver tissue, and real time PCR detected extremely high levels of EBV viremia. EBV infection should be included in the differential diagnoses of hepatitis of unknown etiology, even with unremarkable serologic data.

In vitro reactivation of human immunodeficiency virus-1 upon stimulation with scrub typhus rickettsial infection.

While a number of microbial infections induce a transient burst in viral load in individuals infected with human immunodeficiency virus-1 (HIV-1), a recent study has suggested that scrub typhus may suppress HIV-1 infection. We investigated the effects of Orientia tsutsugamushi on HIV-1 infection. In vitro HIV-1 infection experiments were conducted using peripheral blood mononuclear cells (PBMC) acutely infected with R5 and X4 HIV-1 or PBMC derived from patients receiving highly active antiretroviral therapy (HAART) whose plasma viral load was undetectable. Stimulation of PBMC with O. tsutsugamushi induced production of proinflammatory cytokines and beta-chemokines, and markedly down-regulated expression of CCR5. Although pretreatment with O. tsutsugamushi rendered PBMC resistant to R5 HIV-1, it otherwise enhanced HIV-1 replication. Stimulation by O. tsutsugamushi induced HIV-1 replication in PBMC from patients receiving HAART. These findings suggest that scrub typhus does not necessarily suppress HIV-1 infection and does have potential to enhance HIV-1 replication.

[HIV-suppressive factors].

A number of host and microbial factors have been shown to modulate HIV-1 infection. Their inhibitory effects are either HIV-specific or non-specific, and involve many different kinds of mechanisms. Among anti-HIV host factors are natural ligands or natural antibodies to HIV coreceptors, anti-inflammatory cytokines, interferons and several body fluid components (such as lactoferrin and prostaglandins). Microbial pathogens/factors that may suppress HIV-1 infection include lipopolysaccharide, scrub-typhus rickettsia, human herpesviruses-6 or -7, and GB virus C. While simple application of these HIV-suppressive factors for HIV-infected individuals is not realistic, investigation of mechanisms involved may lead to better understanding of HIV pathogenesis and help establish novel anti-HIV strategy.