Anton M. van Loon

Human parechovirus causes encephalitis with white matter injury in Neonates

To assess the role of human parechoviruses (HPeVs) as a cause of neonatal cerebral infection and to report neuroimaging findings of newborn infants with encephalitis caused by HPeVs.

Severe neonatal parechovirus infection and similarity with enterovirus infection

Background: Enteroviruses (EV) are an important cause of neonatal disease including hepatitis, meningoencephalitis, and myocarditis that can lead to death or severe long-term sequelae. Less is known about severe neonatal infection caused by the parechoviruses (PeV) of which type 1 (PeV1) and type 2 (PeV2) were previously known as echovirus 22 and echovirus 23. They belong to the same family of Picornaviridae as the EV. Of the PeV, so far only PeV3 has been associated in 2 recent reports with severe neonatal infection including involvement of central nervous system. Methods: We compared the clinical signs, diagnosis, laboratory data, cerebral imaging, and neurodevelopmental outcome of 11 neonates with PeV infection with 21 infants with EV infection treated in our hospital between 1994 and 2006. The diagnosis of EV infection or PeV infection was confirmed by a positive EV and/or PeV real time-polymerase chain reaction on blood, cerebrospinal fluid, (CSF) or stool or a viral culture of stool, nasopharyngeal swab, and/or CSF. Results: The 32 infants presented with sepsis-like illness and the most frequent signs were: fever, seizures, irritability, rash, and feeding problems. All patients received antibiotic treatment. Eleven of 21 infants infected with EV and 7 of 11 infants infected with PeV were full-term. Differentiation between the infants infected with EV and PeV on the basis of fever, irritability, rash, and seizures was not possible. Myocarditis was exclusively seen in 4 patients infected by EV. Eight of 11 patients with a PeV infection had meningoencephalitis of whom only 1 infant developed pleocytosis in the CSF. Serum C-reactive protein and CSF protein values were significantly higher in infants with EV infection than in those with PeV infection. Cerebral imaging of all infants with EV or PeV cerebral infection showed mild to severe white matter abnormalities. In 1 infant with EV infection and 3 infants with PeV infection, neurodevelopmental delay occurred. Mortality and long-term sequelae were mainly associated with myocarditis in the infants who were infected with EV (4 of 21). Conclusions: It is not possible to distinguish neonatal PeV from EV infection on the basis of clinical signs. Neonates with PeV or EV infection present with sepsis-like illness and the most frequent signs are fever, seizures, irritability, rash, and feeding problems.

Polymerase chain reaction is more sensitive than viral culture and antigen testing for the detection of respiratory viruses in adults with hematological cancer and pneumonia

Abstract We retrospectively analyzed the value of polymerase chain reaction (PCR) for the detection of respiratory viral infections in 43 patients with hematological cancer whose bronchoalveolar lavage (BAL) samples had been stored. In addition, 17 nose-throat (NT) swabs and 29 blood samples had been obtained. PCR was performed to detect parainfluenza viruses 1–3, respiratory syncytial virus, rhinovirus, influenza viruses A and B, enteroviruses, and coronaviruses. Viral cultures or antigen testing of BAL samples revealed 9 respiratory viruses in 8 patients. By use of PCR, 8 more respiratory viruses were detected in another 7 patients, increasing the rate of identification from 19% to 35% (P < .0005). Available NT swabs yielded the same results with PCR as did BAL samples. We conclude that PCR is more sensitive than viral culture or antigen or serologic testing for detection of respiratory viruses in patients with hematological malignancies, and that it offers the possibility for early, more rapid diagnosis.

Increased Detection of Respiratory Syncytial Virus, Influenza Viruses, Parainfluenza Viruses, and Adenoviruses with Real-Time PCR in Samples from Patients with Respiratory Symptoms

ABSTRACT Respiratory samples (n = 267) from hospitalized patients with respiratory symptoms were tested by real-time PCR, viral culture, and direct immunofluorescence for respiratory syncytial virus, influenza virus, parainfluenza viruses, and adenoviruses. Compared with conventional diagnostic tests, real-time PCR increased the diagnostic yields for these viruses from 24% to 43% and from 3.5% to 36% for children and adults, respectively.

The Prevalence and Incidence of Hepatitis C Virus Infections among Dialysis Patients in The Netherlands: A Nationwide Prospective Study

A nationwide prospective survey on hepatitis C virus (HCV) infections among dialysis patients in The Netherlands was performed. Patients were recruited from 34 dialysis centers and were tested for antibodies and HCV RNA in 1995 and 1997. Seronegative serum samples were analyzed by reverse-transcriptase polymerase chain reaction in pools. HCV-RNA-positive serum samples were genotyped and were partly sequenced. In the first and second rounds, 67 (2.9%) of 2281 and 76 (3.4%) of 2286 patients were HCV positive, respectively. Of 960 patients with paired serum samples, 35 were HCV positive in both rounds, and 9 HCV-positive cases were newly identified in the second round. The incidence of HCV infection was 0.5 per 100 dialysis years. Phylogenetic analysis revealed clustered sequences that indicated nosocomial transmission. Sixty percent of HCV infections, however, can be attributed to 4 interdependent risk factors (i.e., hemodialysis before 1992, kidney transplantation before 1994, and birth or dialysis in a foreign country). In conclusion, the prevalence of HCV infections in The Netherlands does not decline, and transmission within dialysis units continues. Adequate screening of HCV infections and strict enforcement of universal infection control practices are required.

Human herpes virus 6 plasma DNA positivity after hematopoietic stem cell transplantation in children: an important risk factor for clinical outcome.

Human herpes virus 6 (HHV6) is known to reactivate after hematopoietic stem cell transplantation (HSCT), and has been suggested to be associated with severe clinical manifestations in adults. The clinical significance in children remains unclear. We investigated the incidence of HHV6 reactivation in relation to HSCT-associated morbidity and mortality in children. Between January 2004 and May 2006, 58 pediatric patients, median age 7.6 years (range: 0.1-18.1 years), received their first allogeneic HSCT. After HSCT, HHV6, Epstein Barr Virus (EBV), cytomegalovirus (CMV), and adenovirus (AdV)-plasma loads were weekly measured by quantitative PCR. Clinical features, engraftment, graft-versus-host disease (GVHD), and HSCT-associated mortality and morbidity were monitored. HHV6 reactivations were classified in group I (no reactivation), group II (loads <1000 cp/mL) and group III (loads >1000 cp/mL). CMV, EBV, Herpes Simpex Virus, Varicella Zoster Virus, and AdV-reactivations were treated according to local guidelines. HHV6 was treated only when there was clinical suspicion of disease. Thirty-six HLA-identical and 22 HLA nonidentical grafts were transplanted of which 43 were bone marrow or peripheral blood stem cells grafts and 15 were cord blood (CB) grafts. Median follow-up of the patients was 15.5 (1-35) months. HHV6 reactivation occurred in 39 of 58 (67%) patients with 31 of 39 (80%) occurring within the first 30 days post-HSCT. In 26 of 58 (45%) patients (group III), HHV 6 reactivation was significantly associated with higher nonrelapse mortality (P = .02), using multivariate Cox proportional hazard models and grade 2-4 acute GVHD (P = .03) and chronic GVHD (P = .05) in a multivariate logistic regression analysis. HHV6 reactivation is very common after HSCT in children and is associated with serious transplantation-related morbidity and mortality. Although the exact role of HHV6 reactivation after HSCT has to be elucidated, early detection and initiation of therapy might be of benefit.

Frequent Detection of Respiratory Viruses in Adult Recipients of Stem Cell Transplants with the Use of Real-Time Polymerase Chain Reaction, Compared with Viral Culture

Abstract Background. Respiratory virus infections have been recognized as important causes of severe pneumonia in patients who have undergone stem cell transplantation (SCT). Reported incidences of respiratory virus infection in adult SCT recipients vary in the literature from 3.5% to 36% when determined by viral culture. However, a more sensitive method to assess the presence of respiratory viruses in the lower airways may be important for delineation of the true incidence of respiratory virus—associated pneumonia and may be essential for guidance on implementation of antiviral therapy and prevention or limitation of nosocomial spread of infection with respiratory viruses. Methods. To determine the incidence and severity of respiratory tract illness (RTI) and to assess the diagnostic value of real-time reverse-transcriptase polymerase chain reaction (RT-PCR) versus viral culture, 72 SCT recipients were monitored during a 6-month period. Results. A respiratory virus was detected in 21% of episodes of RTI by viral culture and in 63% of RTI episodes by real-time RT-PCR (P < .0001). In lower respiratory tract illness, real-time RT-PCR was much more sensitive than viral culture for detection of respiratory virus (73% vs. 9%; P = .008). The mortality rate for patients with respiratory virus—associated lower respiratory tract illness (25%) was similar to rates reported elsewhere. Respiratory viruses (predominantly rhinovirus) were detected by real-time RT-PCR in 9% of samples obtained from symptom-free SCT recipients at predetermined times by real-time RT-PCR and by viral culture in 1% (P < .0001), indicating that asymptomatic shedding of respiratory viruses also occurs. Conclusion. We conclude that, although asymptomatic shedding of respiratory virus occurs, respiratory viruses are frequent causes of RTI in SCT recipients.

Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study.

Abstract Postherpetic neuralgia (PHN) is the most frequent complication of herpes zoster (HZ) and difficult to treat. Timely identification of high‐risk HZ‐patients enables physicians to focus on PHN prevention. To assess which simple to measure factors are independent predictors of PHN, and whether psychosocial and serological/virological parameters have additional predictive value, a prospective cohort study in primary care was conducted. We included 598 elderly (>50 years) consecutive patients with acute HZ (rash <7 days) below sixth cervical dermatome. At baseline demographic, clinical (e.g., duration and severity of pain and rash), psychological (Pain Cognition List [PCL] and Spielberger’s Anxiety Inventory), serological (VZV‐antibodies) and virological (viremia presence) variables were measured. Blood tests were performed in a random subset of 218 patients. Primary outcome was significant pain (VAS >30 on 0–100 scale) after three months. The final prediction model obtained from multivariable logistic regression was (internally) validated using bootstrapping techniques, and adjusted for optimism. Forty‐six (7.7%) patients developed PHN. Independent predictors were age (odds ratio [OR] = 1.08 per year), acute pain severity (OR = 1.02 per unit), presence of severe rash (OR = 2.31), and rash duration before consultation (OR = 0.78 per day): area under receiver‐operating‐characteristic curve [ROC area] = 0.77 (95% CI: 0.71–0.82). Of the five PCL scores, only factor V (‘trust in healthcare’) was an additional predictor (OR = 1.01 per unit), though it increased the ROC area with only 0.01 to 0.78. The Spielberger’s anxiety scores and serological and virological variables were no additional predictors. Thus, four simple variables can help physicians to timely identify elderly HZ‐patients at risk of PHN.

Rubella Outbreak in the Netherlands, 2004-2005: High Burden of Congenital Infection and Spread to Canada

Background: In The Netherlands and Canada the measles, mumps, rubella vaccine coverage is high. In 2004 a rubella outbreak started in the Netherlands in a population subgroup with low coverage, with subsequent spread to Canada. Methods: We examined data on rubella cases in the Netherlands and Canada reported between September 2004 and July 2005. In The Netherlands we established enhanced surveillance for congenital rubella while in Canada we carried out a cohort study to estimate vaccine effectiveness. Results: In The Netherlands and Canada, 387 and 309 rubella cases were reported, respectively. Of these, 97% were in unvaccinated individuals of orthodox protestant denomination. Reported consequences of rubella in pregnancy were 2 fetal deaths and 14 infants with congenital infection. Of the latter, 11 had clinical defects including deafness in all but eye defects in none. The estimated vaccine effectiveness was 99.3% (95% CI: 95.3%–99.9%). Closely related strains of rubella virus genotype 1G were found in Dutch and Canadian cases. Conclusions: A large rubella outbreak occurred in The Netherlands with spread to Canada in a population subgroup with religious objections to vaccination. Its major public health importance was due to the high burden of congenital disease, international spread and implications for measles and rubella surveillance and elimination. Congenital deafness occurred more frequently and eye defects less frequently than expected. The estimated rubella vaccine effectiveness was very high. Our results demonstrate the risks associated with heterogeneity in rubella vaccine coverage. High rubella vaccine coverage in all population subgroups and sensitive surveillance are crucial for elimination of rubella and CRS.

Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir.

Abstract Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. Some congenitally infected infants will develop sequelae later in life, especially sensorineural hearing loss (SNHL) and mental retardation. There is no generally accepted antiviral therapy for the treatment of symptomatic congenital CMV infections yet. We present a neonate with symptomatic congenital CMV infection, who was treated with intravenous (iv) ganciclovir (GCV) during 18 days and subsequently with oral valganciclovir (VGCV) for 5.5 months, in an attempt to prevent development of SNHL. GCV was given intravenously 10 mg/kg/day in two doses and VGCV doses ranged from 280–850 mg/m2 bidaily (bid). Our experience shows that it is not possible to give a fixed dosing regime for VGCV in neonates and that continuous adaptation of dose is necessary to achieve stable target levels of GCV and to keep the viral load in urine at undetectable level. At 18 months of age no hearing deterioration has occurred. While the current findings are encouraging, the limitations of a single case report with a relatively short follow-up emphasizes the need for further prospective randomized studies to evaluate pharmacokinetics, efficacy and safety of VGCV therapy in neonates with congenital CMV infection.