Elisabeth H. Schölvinck

Upsurge of human enterovirus 68 infections in patients with severe respiratory tract infections

BACKGROUND Enterovirus 68 (EV68) belongs to species Human enterovirus D. It is unique among enteroviruses because it shares properties with human rhinoviruses. After the first isolation in 1962 from four children with respiratory illness, reports of (clusters of) EV68 infections have been rare. During the autumn of 2010, we noticed an upsurge of EV68 infections in the Northern part of the Netherlands in patients with severe respiratory illness. OBJECTIVES To give a detailed description of the clinical and virological data of patients with EV68 infection identified in 2010, and compare these with data collected in 2009. STUDY DESIGN We systematically collected clinical data from patients with an EV68 infection detected in 2010. We added four patients with an EV68 infection from 2009. Further characterization of EV68 was performed by partial sequence analysis of the VP1 genomic region. RESULTS In 2010, EV68 was identified as the only cause of respiratory illness in 24 patients, of which 5 had to be admitted to the intensive care unit. Sequence analysis revealed different lineages in the majority of EV68 detected in 2010 as compared to the 2009 isolates. CONCLUSIONS We noticed an increase of EV68 infections and present clinical as well as sequence data, in which two distinct phylogenetic clusters could be identified.

The emergence of enterovirus D68 in a Dutch University Medical Center and the necessity for routinely screening for respiratory viruses

Abstract Background Since August 2014, an increase in infections caused by enterovirus D68 (EV-D68) was reported in the USA and Canada, for the most part in children presenting with severe respiratory symptoms. Objectives To determine whether an increase in severe EV-D68 respiratory infections was observed in our region. Study design Samples from patients with respiratory symptoms were screened for viral pathogens, including rhinovirus and enterovirus. Subsequently, samples positive for rhinovirus and enterovirus were routinely sequenced for phylogenetic analysis. Furthermore, an additional method was used to detect EV-D68 specifically. Results During the first three quarters of the year 2014, 1896 respiratory samples were analyzed; 39 (2%) of them tested positive for enterovirus. Eighteen samples tested positive for EV-D68, obtained from 16 different patients admitted to our hospital. Eleven were children below the age of 18, of whom five children needed intensive care treatment. The remaining five samples were from adults, who all had an underlying disease; three were transplant patients (heart, lung and renal transplantation), the other two had an underlying lung condition (COPD, asthma). Phylogenetic analysis showed a close relationship with the strains circulating currently in the USA, all belonging to the known EV-D68 genetic subtypes. Conclusions We observed an increase of EV-D68 infections in our population, both in children as well as in adult. In 2014 there have been 16 cases so far, compared to none in 2011 and 2013 and a single case in 2012. Phylogenetic analysis identified two similar clusters as shown in the USA and Canada.

Upsurge of Enterovirus D68, the Netherlands, 2016

In June and July 2016, we identified 8 adults and 17 children with respiratory enterovirus D68 infections. Thirteen children required intensive care unit admission because of respiratory insufficiency, and 1 had concomitant acute flaccid myelitis. Phylogenetic analysis showed that all of 20 sequences obtained belong to the recently described clade B3.

Influenza in the immediate post-pandemic era: A comparison with seasonal and pandemic influenza in hospitalized patients

BACKGROUND Comparative data on severity and treatment of seasonal, pandemic and post-pandemic influenza virus infections are scarce. OBJECTIVES To systematically analyze characteristics of hospitalized patients with influenza in the post-pandemic period compared to seasonal and pandemic influenza. STUDY DESIGN Clinical and virological data of patients hospitalized in a tertiary referral hospital with post-pandemic influenza (2010-2011) were compared with those during seasonal influenza epidemics (2007-2009) and the influenza A(H1N1)pdm09 pandemic (2009-2010). RESULTS 82 patients were admitted during the post-pandemic period, compared to 85 during the pandemic and 60 during seasonal influenza epidemics. No differences were observed in the occurrence of complicated illness and the need for intensive care. However, radiographic pneumonia was significantly more often diagnosed in patients with influenza A(H1N1)pdm09 compared to patients with seasonal influenza A (25% versus 71% in pandemic, p=0.004, and 55% in post-pandemic, p=0.047). Oseltamivir was more frequently prescribed in post-pandemic and pandemic patients compared to previous influenza seasons (48.9% resp. 76.5% versus 6.5%, p<0.0001). During the post-pandemic period, patients with influenza B were significantly less often treated with oseltamivir compared to patients with influenza A (27.0% versus 48.9%, p=0.043), although the course of illness in patients with influenza B was comparable with influenza A. No upsurge of oseltamivir resistance was observed. CONCLUSIONS In our center, severity of illness was comparable for all influenza seasons, although more radiographic pneumonia was diagnosed in patients with influenza A(H1N1)pdm09. Despite the increased use of oseltamivir, no increase in oseltamivir resistance was detected.

Fluordeoxyglucose positron emission tomography contributes to management of pediatric liver transplantation candidates with fever of unknown origin

Fever of unknown origin (FUO) frequently complicates the management of pediatric patients with terminal chronic liver failure during the pretransplantation period and may lead to increased morbidity and mortality. Nonhepatic origins of systemic infections may render the patient unsuitable for transplantation whereas infections within the liver may require organ resection for a cure. Therefore, accurate localization of the infection focus is critical for optimal management of children on the waiting list for liver transplantation. Here we report our experience using [ 18 F]fluordeoxyglucose (FDG)–positron emission tomography (PET) to detect the origin of infection in 11 children with biliary cirrhosis presenting with FUO during the waiting period for liver transplantation. In 5 children, positive intrahepatic FDG‐PET signals correlated with bacterial cultures of the excised liver and/or anatomic or histologic signs of infection. Based on the FDG‐PET findings, these patients underwent transplantation after continuous antibiotic treatment with ongoing, recurrent episodes of fever. In 6 children, no abnormal hepatic FDG‐PET signals were found and no infections could be detected in the liver. Transplantation in these patients was performed only after becoming afebrile. Standard imaging techniques did not reveal abnormalities compatible with infection in any of the children. In conclusion, in children with biliary cirrhosis and FUO on the waiting list for liver transplantation, information obtained by FDG‐PET imaging may be useful for decisions on therapy and suitability for liver transplantation. Liver Transpl 12:1698–1704, 2006.

The significance of rhinovirus detection in hospitalized children: clinical, epidemiological and virological features

Abstract Recent developments in molecular diagnostic tools have led to the easy and rapid detection of a large number of rhinovirus (HRV) strains. However, the lack of clinical and epidemiological data hampers the interpretation of these diagnostic findings. From October 2009 to January 2011, we conducted a prospective study in hospitalized children from whom samples were taken for the detection of respiratory viruses. Clinical, epidemiological and microbiological data from 644 patients with 904 disease episodes were collected. When HRV tested positive, strains were further characterized by sequencing the VP4/VP2 region of the HRV genome. HRV was the single respiratory virus detected in 254 disease episodes (28%). Overall, 99 different serotypes were detected (47% HRV-A, 12% HRV-B, 39% HRV-C). Patients with HRV had more underlying pulmonary illness compared with patients with no virus (p 0.01), or patients with another respiratory virus besides HRV (p 0.007). Furthermore, cough, shortness of breath and a need for oxygen were significantly more present in patients with HRV infection. Particularly, patients with HRV-B required extra oxygen. No respiratory symptom, except for oxygen need, was predictive of the presence of HRV. In 22% of HRV-positive disease episodes, HRV infection was hospital acquired. Phylogenetic analysis revealed several clusters of HRV; in more than 25% of these clusters epidemiological information was suggestive of transmission within specific wards. In conclusion, the detection of HRV may help in explaining respiratory illness, particular in patients with pulmonary co-morbidities. Identifying HRV provides opportunities for timely implementation of infection control measures to prevent intra-hospital transmission.

Low complication rates with totally implantable access port use in epoprostenol treatment of pulmonary hypertension.

BACKGROUND Among patients with advanced pulmonary arterial hypertension (PAH) who are receiving epoprostenol treatment, complications due to the delivery system are known to be a cause of serious morbidity and mortality. In this study, we aimed to outline the complications associated with the use of a totally implantable access port (TIAP) and their consequences in continuous intravenous epoprostenol treatment. METHODS One hundred eleven pulmonary hypertension (PH) patients treated with epoprostenol through a totally implantable access port (TIAP) between May 1998 and July 2006 at three Dutch PH referral centers were retrospectively studied. RESULTS During a mean follow-up period of 946 +/- 719 days, TIAP-related complications included local port site infections, bloodstream infections, port site skin perforations and incorrect port placement, with incidence rates of 0.11, 0.15, 0.06 and 0.04 per patient-year, respectively. Fatal, serious, moderate and minor consequences of these complications had incidence rates of 0.01, 0.50, 0.09 and 0.01 per patient-year, respectively. The median complication-free survival was 371 days. Staphylococcus aureus was the dominant infectious agent. The median TIAP life duration was 677 days. Female patients showed significantly longer first TIAP survival (p = 0.004). CONCLUSIONS The use of a TIAP showed long-lasting port survival and relatively low complication rates. Our data suggest that the TIAP is well suited for continuous intravenous epoprostenol delivery in patients with pulmonary hypertension.

Insufficient Fluconazole Exposure in Pediatric Cancer Patients and the Need for Therapeutic Drug Monitoring in Critically Ill Children

BACKGROUND Fluconazole is recommended as first-line treatment in invasive candidiasis in children and infants. Although timely achievement of adequate exposure of fluconazole improves outcome, therapeutic drug monitoring is currently not recommended. METHODS We conducted a retrospective study of critically ill children treated with fluconazole from January 2007 to October 2013 and for whom fluconazole concentrations were available. We collected demographic, clinical, and treatment data through review of the medical records and determined the correlation of clinical variables with the fluconazole concentration. Additionally, we assessed the relation between the fluconazole concentration and the time to culture conversion in patients with proven invasive candidiasis. RESULTS In total, 99 pediatric patients met the inclusion criteria. The fluconazole concentration was considered subtherapeutic in 40% of the patients. Multiple linear regression analysis showed a significant, independent, and positive association of the fluconazole trough concentration with the fluconazole dose (P <.001), weight (P = .009), and the serum urea concentration (P = .003), and a significant, independent, and negative association with age (P = .004) and cancer as an underlying condition (P = .003). A higher fluconazole concentration was associated with a shorter time to culture conversion (hazard ratio = 1.076 [95% confidence interval, 1.017-1.138]; P = .011). CONCLUSIONS The fluconazole concentration is not sufficient in pediatric cancer patients with the currently recommended dose regimen, and a higher fluconazole dose is required to achieve adequate drug exposure. Therapeutic drug monitoring of fluconazole can be a valuable tool to detect possible underexposure in critically ill children.

Implementing tuberculosis entry screening for asylum seekers: the Groningen experience

For 3 years, Europe has faced an increasing refugee crisis in which hundreds of thousands of displaced persons are risking their lives to seek a safer and better future in the European Union (EU). Many of these migrants originate from highly tuberculosis (TB)-endemic countries. Furthermore, their travel conditions are often poor, allowing potential transmission of infectious diseases, including TB. The Netherlands have observed an increased influx of asylum seekers since 2012 too, with fluctuating numbers every month, and a sharp increase in the summer of 2015, putting constraints on the process of registration, identification, application and accommodation, including mandatory radiographic screening for intrathoracic TB. We describe the impact of such migration on the Public Health TB Clinic of Groningen (responsible for nearly all TB entry screening for asylum seekers in the Netherlands), and our flexible and efficient practice model for daily radiographic TB screening. We report the yield of this intervention over the last 4 years, and reflect on issues concerning entry screening. The Dutch practice model for radiographic TB screening of asylum seekers has proved feasible http://ow.ly/Z1QTP

Loss of ADAM17 is associated with severe multiorgan dysfunction

ADAM metallopeptidase domain 17 (ADAM17) is responsible for processing large numbers of proteins. Recently, 1 family involving 2 patients with a homozygous mutation in ADAM17 were described, presenting with skin lesions and diarrhea. In this report, we describe a second family confirming the existence of this syndrome. The proband presented with severe diarrhea, skin rash, and recurrent sepsis, eventually leading to her death at the age of 10 months. We performed exome sequencing and detailed pathological and immunological investigations. We identified a novel homozygous frameshift mutation in ADAM17 (NM_003183.4:c.308dupA) leading to a premature stop codon. CD4(+) and CD8(+) T-cell stimulation assays showed severely diminished tumor necrosis factor-α and interleukin-2 production. Skin biopsies indicated a focal neutrophilic infiltrate and spongiotic dermatitis. Interestingly, the patient developed unexplained systolic hypertension and nonspecific hepatitis with apoptosis. This report provides evidence for an important role of ADAM17 in human immunological response and underscores its multiorgan involvement.