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Professor Adilia Warris
Professor (Clinical) (Deputy Centre Director MRC CMM)
I am a professor in paediatric infectious diseases with a specific interest in medical mycology. I am co-director of the MRC Centre for Medical Mycology at the University of Exeter and a consultant in paediatric infectious diseases in Great Ormond Street Hospital, London.
My research profile has a strong translational focus and specific areas of interest include the host-fungus interaction in specific patient groups with an emphasis on Aspergillus species; the unique interaction of A. nidulans and the CGD host, Aspergillus infections in people with cystic fibrosis, the development of new management strategies for invasive fungal disease in children, the epidemiology of invasive fungal infections in children, and the pharmacology of antifungals in paediatrics.
I chair the European Paediatric Mycology Network (EPMyN) through which post-graduate courses in Paediatric Mycology are coordinated as well as multi-center European studies to obtain a better insight in the fungal and clinical epidemiology of fungal infections in neonates and children. I am leading the Fungal Infection Scientific Content Area within PENTA Child Health. I am the Chief Investigator of cASPerCF, one of the investigator-led studies in the conect4children (C4C) network funded by the EU. The cASPerCF study aims to describe the epidemiology of Aspergillus infections in childeren and young adults with cystic fibrosis and to validate a posaconazole dosing algorithm to treat those infections. Additional ongoing studies are focussing on the fungal and clinical epidemiology of invasive fungal diseases in neonates and children (EPMyN-EUROCANDY study), and paediatric antifungal stewardship (PASOAP study).
1994 MD, University of Groningen, the Netherlands
2004 PhD Medical Science, Radboud University Nijmegen, the Netherlands
2014 Fellow of the Royal College of Paediatrics and Child Health
2018 Fellow of the Academy of the European Council Medical Mycology
2003 Paediatrician
2005-2012 Consultant Paediatric Infectious Diseases & Immunology, Radboud University Nijmegen, the Netherlands
2009 Visiting Research Fellow, National Institutes of Health, Bethesda, MD, US
2012-2013 Associate Professor Paediatric Infectious Diseases & Immunology, Radboud University Nijmegen, the Netherlands
2013 Clinical Reader Medical Mycology, University of Aberdeen, UK
2013-2019 Honorary Consultant Paediatric Infectious Diseases, Royal Aberdeen Children's Hospital, UK
2015-2019 Personal Chair, University of Aberdeen, UK
2019 Consultant Paediatric Infectious Diseases, Great Ormond Street Hospital, London
My research is aimed at unravelling unique host-fungus interactions based on clinical observations.
Patients with chronic granulomatous disease (CGD), suffering from an inborn error in the function of white blood cells, have an extremely high-risk to develop invasive aspergillosis and often these infections are fatal. Invasive aspergillosis in patients with CGD is caused by 2 different Aspergillus species, Aspergillus fumigatus and Aspergillus nidulans, with the latter having a unique predilection for this specific patient group. Our studies are focussed on the molecular interaction between immune cells from CGD patients and those fungi, with the ultimate goal to find new targets to improve treatment. In addition we are researching how A. fumigatus can persist and adapt in the lungs of patients with CGD, leading to recurrent infections and the fungus becoming resistant to antifungal therapy.
Comparable studies are done with immune cells from people with cystic fibrosis (CF). Half of the people with CF will be infected with A. fumigatus in their lungs leading to exacerbation of lung disease. The pathophysiology of Aspergillus infections in people with CF is not well understood and next to the presence of the thick sticky mucus entrapping the fungal spores in the lungs of people with CF, their immune cells respond abnormally to the presence of A. fumigatus. By studying the interaction between CF immune cells and A. fumigatus we aim to increase our insight in this specific host-fungus interactions and to find new treatment modalities to preserve lung function.
dr Emily Chesshyre, clinical research fellow
dr Laura Ferreras-Antolin, clinical research fellow
Alex Currie, PhD student
Elliot Mahony, PhD student
dr Harshani Tabrew, visiting clinical fellow (Sri Lanka)
dr Naamal Jayawardena, visiting clinical fellow (Sri Lanka)
Chief Investigator of the cASPerCF study, a connect4children proof-of-viability study (conect4children.org) funded by IMI-2 (Innovative Medicines Initiative 2).
Co-investigator of the Strategic Research Centre TrIFIC consortium (trific.org) funded by the UK CF Trust.
Lead of the Fungal Infection Working Group of Penta Child Health (penta-id.org)
Tenbrink T, Stell J, Galton A, Wood Z (2013). Preface.
Warris A, De Groot R (2006). Human metapneumovirus: an important cause of acute respiratory illness.
Nooitgedagt JE, Warris A, Liem KDD, van t Hek L, Henriet SS (In Press). Kinkhoest bij jonge zuigelingen: een gevaarlijke ziekte met aspecifieke verschijnselen. Nederlands tijdschrift voor geneeskunde, 157
Kinkhoest bij jonge zuigelingen: een gevaarlijke ziekte met aspecifieke verschijnselen
Pertussis, or whooping cough, caused by Bordetella pertussis, still occurs despite vaccination. Most of the cases occurring in adolescents and adults are mild or have a subclinical course, but these patients can be a source of transmission to unvaccinated or partially vaccinated infants. Symptoms of infant pertussis are often not specific, but pertussis can be fatal. In this article, we present one case of unvaccinated twins who each presented with initial signs of a viral respiratory disease. Within a few days, each developed rapidly progressive respiratory failure complicated by refractory pulmonary hypertension due to malignant pertussis. Both patients died eventually. It is important for paediatricians, general practitioners, midwives and gynaecologists to be alert to coughing in their patients. More efficient vaccination strategies should be discussed to prevent both the transmission of B. pertussis and the occurrence of severe and fatal pertussis in young infants.
Lutsar I, Chazallon C, Trafojer U, Meiffredy de Cabre V, Auriti C, Bertaina C, Calo Carducci FI, Canpolat FE, Esposito S, Fournier I, et al (In Press). Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): a randomised controlled trial.
Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): a randomised controlled trial
AbstractBackgroundThe early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, were single centre or country, insufficiently powered, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad spectrum antibiotic is superior to standard of care regimen (SOC) in empiric treatment of LOS and thus aimed to compare the efficacy and safety of meropenem to SOC in infants aged <90 days with LOS.Methods and findingsNeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or SOC (ampicillin+gentamicin or cefotaxime+gentamicin) for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and day 28 for meropenem-resistant Gram-negative organisms (CRGNO).The primary analysis was performed in all randomised patients (full analysis set) and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors.From September 3rd 2012 to November 30th 2014, in total 136 patients in each arm were randomized; 140 (52%) were culture positive. Success at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p=0.087); 17/63 (27%) vs. 10/77 (13%) in patients with positive cultures (p=0.022). The main reason of failure was modification of allocated therapy. Adverse events occurred in 72% and serious adverse events in 17% of patients, the mortality rate was 6% with no differences between study arms. Cumulative acquisition of CRGNO by day 28 occurred in 4% in the meropenem and 12% in the SOC arm (p=0.052).ConclusionsMeropenem was not superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality and did not outselect colonization with CRGNOs. Meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing ESBL and AmpC beta-lactamases are circulating.
Warris A, Armstrong-James D (2022). Antifungal therapy for chronic pulmonary aspergillosis. Lancet Infect Dis, 22(7), 924-926. Author URL.
Ferreras-Antolín L, Irwin A, Atra A, Chapelle F, Drysdale SB, Emonts M, McMaster P, Paulus S, Patel S, Rompola M, et al (2022). Pediatric Antifungal Prescribing Patterns Identify Significant Opportunities to Rationalize Antifungal Use in Children. Pediatr Infect Dis J, 41(3), e69-e74.
Pediatric Antifungal Prescribing Patterns Identify Significant Opportunities to Rationalize Antifungal Use in Children.
OBJECTIVE: the need for pediatric antifungal stewardship programs has been driven by an increasing consumption of antifungals for prophylactic and empirical use. Drivers and rational of antifungal prescribing need to be identified to optimize prescription behaviors. METHODS: a prospective modified weekly Point Prevalence Survey capturing antifungal prescriptions for children (> 90 days to < 18 years of age) in 12 centers in England during 26 consecutive weeks was performed. Demographic, diagnostic and treatment information was collected for each patient. Data were entered into an online REDCap database. RESULTS: One thousand two hundred fifty-eight prescriptions were included for 656 pediatric patients, 44.9% were girls, with a median age of 6.4 years (interquartile range, 2.5-11.3). Most common underlying condition was malignancy (55.5%). Four hundred nineteen (63.9%) received antifungals for prophylaxis, and 237 (36.1%) for treatment. Among patients receiving antifungal prophylaxis, 40.2% did not belong to a high-risk group. In those receiving antifungal treatment, 45.9%, 29.4%, 5.1% and 19.6% had a diagnosis of suspected, possible, probable of proven invasive fungal disease (IFD), respectively. Proven IFD was diagnosed in 78 patients, 84.6% (n = 66) suffered from invasive candidiasis and 15.4% (n = 12) from an invasive mold infection. Liposomal amphotericin B was the most commonly prescribed antifungal for both prophylaxis (36.6%) and empiric and preemptive treatment (47.9%). Throughout the duration of the study, 72 (11.0%) patients received combination antifungal therapy. CONCLUSIONS: Antifungal use in pediatric patients is dominated by liposomal amphotericin B and often without evidence for the presence of IFD. A significant proportion of prophylactic and empiric antifungal use was seen in pediatric patients not at high-risk for IFD.
Helmstetter N, Chybowska AD, Delaney C, Da Silva Dantas A, Gifford H, Wacker T, Munro C, Warris A, Jones B, Cuomo CA, et al (2022). Population genetics and microevolution of clinical Candida glabrata reveals recombinant sequence types and hyper-variation within mitochondrial genomes, virulence genes, and drug targets. Genetics, 221(1).
Population genetics and microevolution of clinical Candida glabrata reveals recombinant sequence types and hyper-variation within mitochondrial genomes, virulence genes, and drug targets.
Candida glabrata is the second most common etiological cause of worldwide systemic candidiasis in adult patients. Genome analysis of 68 isolates from 8 hospitals across Scotland, together with 83 global isolates, revealed insights into the population genetics and evolution of C. glabrata. Clinical isolates of C. glabrata from across Scotland are highly genetically diverse, including at least 19 separate sequence types that have been recovered previously in globally diverse locations, and 1 newly discovered sequence type. Several sequence types had evidence for ancestral recombination, suggesting transmission between distinct geographical regions has coincided with genetic exchange arising in new clades. Three isolates were missing MATα1, potentially representing a second mating type. Signatures of positive selection were identified in every sequence type including enrichment for epithelial adhesins thought to facilitate fungal adhesin to human epithelial cells. In patent microevolution was identified from 7 sets of recurrent cases of candidiasis, revealing an enrichment for nonsynonymous and frameshift indels in cell surface proteins. Microevolution within patients also affected epithelial adhesins genes, and several genes involved in drug resistance including the ergosterol synthesis gene ERG4 and the echinocandin target FKS1/2, the latter coinciding with a marked drop in fluconazole minimum inhibitory concentration. In addition to nuclear genome diversity, the C. glabrata mitochondrial genome was particularly diverse, with reduced conserved sequence and conserved protein-encoding genes in all nonreference ST15 isolates. Together, this study highlights the genetic diversity within the C. glabrata population that may impact virulence and drug resistance, and 2 major mechanisms generating this diversity: microevolution and genetic exchange/recombination.
Rhodes J, Abdolrasouli A, Dunne K, Sewell TR, Zhang Y, Ballard E, Brackin AP, van Rhijn N, Chown H, Tsitsopoulou A, et al (2022). Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment. Nat Microbiol, 7(5), 663-674.
Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment.
Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus isolates from across the UK and Ireland (comprising 153 clinical isolates from 143 patients and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (A and B) with little interclade recombination and the majority of environmental azole resistance found within clade A. Second, we show occurrences where azole-resistant isolates of near-identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-wide scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, while other regions under selection have no defined function. Lastly, pan-genome analysis identified genes linked to azole resistance and previously unknown resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.
Rhodes J, Abdolrasouli A, Dunne K, Sewell TR, Zhang Y, Ballard E, Brackin AP, van Rhijn N, Chown H, Tsitsopoulou A, et al (2022). Publisher Correction: Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment. Nat Microbiol, 7(11). Author URL.
Ferreras-Antolin L, Borman A, Diederichs A, Warris A, Lehrnbecher T (2022). Serum Beta-D-Glucan in the Diagnosis of Invasive Fungal Disease in Neonates, Children and Adolescents: a Critical Analysis of Current Data. Journal of Fungi, 8(12).
Fisher MC, Alastruey-Izquierdo A, Berman J, Bicanic T, Bignell EM, Bowyer P, Bromley M, Brüggemann R, Garber G, Cornely OA, et al (2022). Tackling the emerging threat of antifungal resistance to human health. Nat Rev Microbiol, 20(9), 557-571.
Tackling the emerging threat of antifungal resistance to human health.
Invasive fungal infections pose an important threat to public health and are an under-recognized component of antimicrobial resistance, an emerging crisis worldwide. Across a period of profound global environmental change and expanding at-risk populations, human-infecting pathogenic fungi are evolving resistance to all licensed systemic antifungal drugs. In this Review, we highlight the main mechanisms of antifungal resistance and explore the similarities and differences between bacterial and fungal resistance to antimicrobial control. We discuss the research and innovation topics that are needed for risk reduction strategies aimed at minimizing the emergence of resistance in pathogenic fungi. These topics include links between the environment and One Health, surveillance, diagnostics, routes of transmission, novel therapeutics and methods to mitigate hotspots for fungal adaptation. We emphasize the global efforts required to steward our existing antifungal armamentarium, and to direct the research and development of future therapies and interventions.
Groll AH, Pana D, Lanternier F, Mesini A, Ammann RA, Averbuch D, Castagnola E, Cesaro S, Engelhard D, Garcia-Vidal C, et al (2021). 8th European Conference on Infections in Leukaemia: 2020 guidelines for the diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or post-haematopoietic cell transplantation. Lancet Oncol, 22(6), e254-e269.
8th European Conference on Infections in Leukaemia: 2020 guidelines for the diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or post-haematopoietic cell transplantation.
Paediatric patients with cancer and those undergoing allogeneic haematopoietic cell transplantation have an increased susceptibility to invasive fungal diseases. In addition to differences in underlying conditions and comorbidities relative to adults, invasive fungal diseases in infants, children, and adolescents are unique in terms of their epidemiology, the validity of current diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of phase 3 clinical trials to provide data to guide evidence-based interventions. To re-examine the state of knowledge and to further improve invasive fungal disease diagnosis, prevention, and management, the 8th European Conference on Infections in Leukaemia (ECIL-8) reconvened a Paediatric Group to review the literature and to formulate updated recommendations according to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) grading system, which are summarised in this Review.
Lehrnbecher T, Averbuch D, Castagnola E, Cesaro S, Ammann RA, Garcia-Vidal C, Kanerva J, Lanternier F, Mesini A, Mikulska M, et al (2021). 8th European Conference on Infections in Leukaemia: 2020 guidelines for the use of antibiotics in paediatric patients with cancer or post-haematopoietic cell transplantation. Lancet Oncol, 22(6), e270-e280.
8th European Conference on Infections in Leukaemia: 2020 guidelines for the use of antibiotics in paediatric patients with cancer or post-haematopoietic cell transplantation.
Paediatric patients with cancer and those undergoing haematopoietic cell transplantation are at high risk of bacterial infections. The 8th European Conference on Infections in Leukaemia (ECIL-8) convened a Paediatric Group to review the literature and to formulate recommendations for the use of antibiotics according to the European Society of Clinical Microbiology and Infectious Diseases grading system. The evaluation of antibacterial prophylaxis included mortality, bloodstream infection, febrile neutropenia, emergence of resistance, and adverse effects as endpoints. Initial antibacterial therapy and antibiotic de-escalation or discontinuation focused on patients with a clinically stable condition and without previous infection or colonisation by resistant bacteria, and on patients with a clinically unstable condition or with previous infection or colonisation by resistant bacteria. The final considerations and recommendations of the ECIL-8 Paediatric Group on antibacterial prophylaxis, initial therapy, and de-escalation strategies are summarised in this Policy Review.
Zelante T, Choera T, Beauvais A, Fallarino F, Paolicelli G, Pieraccini G, Pieroni M, Galosi C, Beato C, De Luca A, et al (2021). Aspergillus fumigatus tryptophan metabolic route differently affects host immunity. Cell Rep, 34(4).
Aspergillus fumigatus tryptophan metabolic route differently affects host immunity.
Indoleamine 2,3-dioxygenases (IDOs) degrade l-tryptophan to kynurenines and drive the de novo synthesis of nicotinamide adenine dinucleotide. Unsurprisingly, various invertebrates, vertebrates, and even fungi produce IDO. In mammals, IDO1 also serves as a homeostatic regulator, modulating immune response to infection via local tryptophan deprivation, active catabolite production, and non-enzymatic cell signaling. Whether fungal Idos have pleiotropic functions that impact on host-fungal physiology is unclear. Here, we show that Aspergillus fumigatus possesses three ido genes that are expressed under conditions of hypoxia or tryptophan abundance. Loss of these genes results in increased fungal pathogenicity and inflammation in a mouse model of aspergillosis, driven by an alternative tryptophan degradation pathway to indole derivatives and the host aryl hydrocarbon receptor. Fungal tryptophan metabolic pathways thus cooperate with the host xenobiotic response to shape host-microbe interactions in local tissue microenvironments.
Warris A, Schwartz I (2021). Editorial MMCR special issue 'Covid-19 associated pulmonary aspergillosis'. Med Mycol Case Rep, 31 Author URL.
Ferreras-Antolin L, Bielicki J, Warris A, Sharland M, Hsia Y, GARPEC Network (2021). Global Divergence of Antifungal Prescribing Patterns: Data from the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children Surveys. Pediatr Infect Dis J, 40(4), 327-332.
Global Divergence of Antifungal Prescribing Patterns: Data from the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children Surveys.
BACKGROUND: Globally, invasive fungal diseases (IFDs) have a significant impact in human health. With an increasing pediatric population at risk of IFD, effective antifungal drugs access and affordability should be ensured universally. The aim of our study was to characterize the global antifungal drug use in neonates and children and its variability between countries in different income groups. METHODS: Data were extracted from the Global Antimicrobial Resistance, Prescribing and Efficacy in Neonates and Children Point Prevalence Survey project, consisting in 1 pilot and four 1-day Point Prevalence Survey between 2015 and 2017. The data had been entered through a study-specific web-based data collection tool. RESULTS: from a total of 13,410 children included, 7.8% (1048/13,410) received at least 1 systemic antifungal drug: 9.5% (95% confidence interval: 8.9%-10.1%) in high income countries (HIC) versus 5.0% (95% confidence interval: 4.4%-5.6%) in low-middle income countries (LMIC) (P < 0.01). A significant proportion of patients on antifungals belonged to high-risk group for IFD (67.4%; 706/1048); most of these were managed in HIC (72.8%, P < 0.01). The likelihood of receiving antifungals being in high-risk group was higher in HIC compared with LMIC (ratio of 5.8 vs. 3.4, P < 0.01). Antifungal prophylaxis was more likely prescribed in HIC (67.2% vs. 30.4%, P < 0.01). Fluconazole was the most frequently prescribed drug. The proportional use of fluconazole was higher in LMIC compared with HIC. CONCLUSIONS: a significant variability of antifungal prescribing patterns was observed. The proportional use of systemic antifungals was twice as high in HIC compared with LMIC. More detailed data on access and antifungal use in limited-resource settings should be explored.
Hoenigl M, Salmanton-García J, Walsh TJ, Nucci M, Neoh CF, Jenks JD, Lackner M, Sprute R, Al-Hatmi AMS, Bassetti M, et al (2021). Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology. Lancet Infect Dis, 21(8), e246-e257.
Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology.
With increasing numbers of patients needing intensive care or who are immunosuppressed, infections caused by moulds other than Aspergillus spp or Mucorales are increasing. Although antifungal prophylaxis has shown effectiveness in preventing many invasive fungal infections, selective pressure has caused an increase of breakthrough infections caused by Fusarium, Lomentospora, and Scedosporium species, as well as by dematiaceous moulds, Rasamsonia, Schizophyllum, Scopulariopsis, Paecilomyces, Penicillium, Talaromyces and Purpureocillium species. Guidance on the complex multidisciplinary management of infections caused by these pathogens has the potential to improve prognosis. Management routes depend on the availability of diagnostic and therapeutic options. The present recommendations are part of the One World-One Guideline initiative to incorporate regional differences in the epidemiology and management of rare mould infections. Experts from 24 countries contributed their knowledge and analysed published evidence on the diagnosis and treatment of rare mould infections. This consensus document intends to provide practical guidance in clinical decision making by engaging physicians and scientists involved in various aspects of clinical management. Moreover, we identify areas of uncertainty and constraints in optimising this management.
Hatinguais R, Pradhan A, Brown GD, Brown AJP, Warris A, Shekhova E (2021). Mitochondrial Reactive Oxygen Species Regulate Immune Responses of Macrophages to Aspergillus fumigatus. Front Immunol, 12
Mitochondrial Reactive Oxygen Species Regulate Immune Responses of Macrophages to Aspergillus fumigatus.
Reactive Oxygen Species (ROS) are highly reactive molecules that can induce oxidative stress. For instance, the oxidative burst of immune cells is well known for its ability to inhibit the growth of invading pathogens. However, ROS also mediate redox signalling, which is important for the regulation of antimicrobial immunity. Here, we report a crucial role of mitochondrial ROS (mitoROS) in antifungal responses of macrophages. We show that mitoROS production rises in murine macrophages exposed to swollen conidia of the fungal pathogen Aspergillus fumigatus compared to untreated macrophages, or those treated with resting conidia. Furthermore, the exposure of macrophages to swollen conidia increases the activity of complex II of the respiratory chain and raises mitochondrial membrane potential. These alterations in mitochondria of infected macrophages suggest that mitoROS are produced via reverse electron transport (RET). Significantly, preventing mitoROS generation via RET by treatment with rotenone, or a suppressor of site IQ electron leak, S1QEL1.1, lowers the production of pro-inflammatory cytokines TNF-α and IL-1β in macrophages exposed to swollen conidia of A. fumigatus. Rotenone and S1QEL1.1 also reduces the fungicidal activity of macrophages against swollen conidia. Moreover, we have established that elevated recruitment of NADPH oxidase 2 (NOX2, also called gp91phox) to the phagosomal membrane occurs prior to the increase in mitoROS generation. Using macrophages from gp91phox-/- mice, we have further demonstrated that NOX2 is required to regulate cytokine secretion by RET-associated mitoROS in response to infection with swollen conidia. Taken together, these observations demonstrate the importance of RET-mediated mitoROS production in macrophages infected with A. fumigatus.
Macinnes R, Warris A (2021). Paediatric histoplasmosis 2000–2019: a review of 83 cases. Journal of Fungi, 7(6).
Paediatric histoplasmosis 2000–2019: a review of 83 cases
Histoplasmosis is an endemic fungal infection that is confined to specific geographical regions. Histoplasma spp. are primary pathogens that cause disease in both immunocompetent and immunocompromised patients, ranging from a single-organ (mostly affecting the lungs) infection to life-threatening disseminated disease. Knowledge about the clinical epidemiology relies on data from adult populations; little is known about the patient and disease characteristics in the paediatric population. Therefore, a structured review of published cases of paediatric histoplasmosis between 2000 and 2019 was performed. A literature search of PubMed was conducted and the epidemiological and clinical data from 83 cases were analysed. The mean age at presentation was 9.5 ± 5.5 years, and 51% were girls. Two-thirds of the children were immunocompromised. The majority of children presented with disseminated disease. The most frequently observed clinical symptoms were respiratory symptoms, alongside non-specific systemic features, including fever, myalgia, fatigue and weight loss. The mortality rate was 11%. Histoplasmosis affects children of any age. Being immunocompromised is a risk factor for severe and disseminated disease. The lack of specific presenting features leads to underreporting and delay in diagnosis. To improve the recognition and outcome of histoplasmosis in childhood, increased awareness and surveillance systems are warranted.
Cruciani M, White PL, Mengoli C, Löffler J, Morton CO, Klingspor L, Buchheidt D, Maertens J, Heinz WJ, Rogers TR, et al (2021). The impact of anti-mould prophylaxis on Aspergillus PCR blood testing for the diagnosis of invasive aspergillosis. J Antimicrob Chemother, 76(3), 635-638.
The impact of anti-mould prophylaxis on Aspergillus PCR blood testing for the diagnosis of invasive aspergillosis.
BACKGROUND: the performance of the galactomannan enzyme immunoassay (GM-EIA) is impaired in patients receiving mould-active antifungal therapy. The impact of mould-active antifungal therapy on Aspergillus PCR testing needs to be determined. OBJECTIVES: to determine the influence of anti-mould prophylaxis (AMP) on the performance of PCR blood testing to aid the diagnosis of proven/probable invasive aspergillosis (IA). METHODS: As part of the systematic review and meta-analysis of 22 cohort studies investigating Aspergillus PCR blood testing in 2912 patients at risk of IA, subgroup analysis was performed to determine the impact of AMP on the accuracy of Aspergillus PCR. The incidence of IA was calculated in patients receiving and not receiving AMP. The impact of two different positivity thresholds (requiring either a single PCR positive test result or ≥2 consecutive PCR positive test results) on accuracy was evaluated. Meta-analytical pooling of sensitivity and specificity was performed by logistic mixed-model regression. RESULTS: in total, 1661 (57%) patients received prophylaxis. The incidence of IA was 14.2%, significantly lower in the prophylaxis group (11%-12%) compared with the non-prophylaxis group (18%-19%) (P
Ballard E, Yucel R, Melchers WJG, Brown AJP, Verweij PE, Warris A (2020). Antifungal Activity of Antimicrobial Peptides and Proteins against Aspergillus fumigatus. J Fungi (Basel), 6(2).
Antifungal Activity of Antimicrobial Peptides and Proteins against Aspergillus fumigatus.
Antimicrobial peptides and proteins (AMPs) provide an important line of defence against invading microorganisms. However, the activity of AMPs against the human fungal pathogen Aspergillus fumigatus remains poorly understood. Therefore, the aim of this study was to characterise the anti-Aspergillus activity of specific human AMPs, and to determine whether A. fumigatus can possess resistance to specific AMPs, as a result of in-host adaptation. AMPs were tested against a wide range of clinical isolates of various origins (including cystic fibrosis patients, as well as patients with chronic and acute aspergillosis). We also tested a series of isogenic A. fumigatus isolates obtained from a single patient over a period of 2 years. A range of environmental isolates, obtained from soil in Scotland, was also included. Firstly, the activity of specific peptides was assessed against hyphae using a measure of fungal metabolic activity. Secondly, the activity of specific peptides was assessed against germinating conidia, using imaging flow cytometry as a measure of hyphal growth. We showed that lysozyme and histones inhibited hyphal metabolic activity in all the A. fumigatus isolates tested in a dose-dependent fashion. In addition, imaging flow cytometry revealed that histones, β-defensin-1 and lactoferrin inhibited the germination of A. fumigatus conidia.
Currie AJ, Main ET, Wilson HM, Armstrong-James D, Warris A (2020). CFTR Modulators Dampen Aspergillus-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes. Frontiers in Cellular and Infection Microbiology, 10
CFTR Modulators Dampen Aspergillus-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes
Excessive inflammation by phagocytes during Aspergillus fumigatus infection is thought to promote lung function decline in CF patients. CFTR modulators have been shown to reduce A. fumigatus colonization in vivo, however, their antifungal and anti-inflammatory mechanisms are unclear. Other treatments including azithromycin and acebilustat may dampen Aspergillus-induced inflammation due to their immunomodulatory properties. Therefore, we set out in this study to determine the effects of current CF therapies on ROS production and fungal killing, either direct or indirect by enhancing antifungal immune mechanisms in peripheral blood immune cells from CF patients upon A. fumigatus infection. Isolated peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) from CF patients and healthy volunteers were challenged with A. fumigatus following pre-treatment with CFTR modulators, azithromycin or acebilustat. Ivacaftor/lumacaftor treated CF and control subject PMNs resulted in a significant reduction (p < 0.05) in Aspergillus-induced ROS. For CF PBMC, Aspergillus-induced ROS was significantly reduced when pre-treated with ivacaftor alone (p < 0.01) or in combination with lumacaftor (p < 0.01), with a comparable significant reduction in control subject PBMC (p < 0.05). Azithromycin and acebilustat had no effect on ROS production by CF or control subject phagocytes. None of the treatments showed an indirect or direct antifungal activity. In summary, CFTR modulators have potential for additional immunomodulatory benefits to prevent or treat Aspergillus-induced inflammation in CF. The comparable effects of CFTR modulators observed in phagocytes from control subjects questions their exact mechanism of action.
Lehrnbecher T, Fisher BT, Phillips B, Beauchemin M, Carlesse F, Castagnola E, Duong N, Dupuis LL, Fioravantti V, Groll AH, et al (2020). Clinical Practice Guideline for Systemic Antifungal Prophylaxis in Pediatric Patients with Cancer and Hematopoietic Stem-Cell Transplantation Recipients. J Clin Oncol, 38(27), 3205-3216.
Clinical Practice Guideline for Systemic Antifungal Prophylaxis in Pediatric Patients with Cancer and Hematopoietic Stem-Cell Transplantation Recipients.
PURPOSE: to develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients. METHODS: Recommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients. RESULTS: There were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made. CONCLUSION: We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps.
Warris A, Pana Z-D, Oletto A, Lundin R, Castagnola E, Lehrnbecher T, Groll AH, Roilides E, EUROCANDY Study Group (2020). Etiology and Outcome of Candidemia in Neonates and Children in Europe: an 11-year Multinational Retrospective Study. Pediatr Infect Dis J, 39(2), 114-120.
Etiology and Outcome of Candidemia in Neonates and Children in Europe: an 11-year Multinational Retrospective Study.
BACKGROUND: Data on Candida bloodstream infections in pediatric patients in Europe are limited. We performed a retrospective multicenter European study of the epidemiology and outcome of neonatal and pediatric candidemia. MATERIAL AND METHODS: all first positive blood cultures from patients ≤ 18 years of age with candidemia were registered. Patients' demographic and clinical characteristics and causative Candida species were collected and analyzed. Regression analysis was used to identify factors independently associated with mortality. RESULTS: One thousand three hundred ninety-five episodes of candidemia (57.8% male) were reported from 23 hospitals in 10 European countries. of the 1395 episodes, 36.4% occurred in neonates (≤ 44 weeks postmenstrual age), 13.8% in infants (> 44 weeks postmenstrual age to 1 year) and 49.8% in children and adolescents. Candida albicans (52.5%) and Candida parapsilosis (28%) were the predominant species. A higher proportion of candidemia caused by C. albicans was observed among neonatal patients (60.2%) with highest rates of C. parapsilosis seen among infants (42%). Children admitted to hematology-oncology wards presented the highest rates of non-albicans Candida species. Candidemia because of C. albicans was more frequent than non-albicans Candida in Northern versus Southern Europe (odds ratio, 2.3; 95% confidence interval, 1.8-2.9; P < 0.001). The all-cause mortality at 30 days was 14.4%. All-cause mortality was higher among patients admitted to the neonatal or pediatric intensive care units than other wards. Over time, no significant changes in species distribution were observed. CONCLUSIONS: This first multicenter European study shows unique characteristics of the epidemiology of pediatric candidemia. The insights obtained from this study will be useful to guide clinical management and antifungal stewardship.
Lutsar I, Chazallon C, Trafojer U, de Cabre VM, Auriti C, Bertaina C, Calo Carducci FI, Canpolat FE, Esposito S, Fournier I, et al (2020). Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): a randomised controlled trial. PLoS One, 15(3).
Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): a randomised controlled trial.
BACKGROUND: the early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged 44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). CONCLUSIONS: Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.
Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, Clancy CJ, Wingard JR, Lockhart SR, Groll AH, et al (2020). Revision and Update of the Consensus Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis, 71(6), 1367-1376.
Revision and Update of the Consensus Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.
BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: to achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.
Warris A, Bercusson A, Armstrong-James D (2019). Aspergillus colonization and antifungal immunity in cystic fibrosis patients. Med Mycol, 57(Supplement_2), S118-S126.
Aspergillus colonization and antifungal immunity in cystic fibrosis patients.
Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is the most common inherited life-limiting disease in North European people affecting 90,000 people worldwide. Progressive lung damage caused by recurrent infection and chronic airway inflammation is the major determinant of survival with a median age at death of 29 years. Approximately 60% of CF patients are infected with Aspergillus fumigatus, a ubiquitous environmental fungus, and its presence has been associated with accelerated lung function decline. Half of the patients infected with Aspergillus are
White PL, Barnes RA, Gorton R, Cruciani M, Loeffler J, Alanio A, Bialek R, Bretagne S, Buchheidt D, Serna MJB, et al (2019). Comment on: T2Candida MR as a predictor of outcome in patients with suspected invasive candidiasis starting empirical antifungal treatment: a prospective pilot study. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 74(2), 532-533. Author URL.
Akase IE, Olowoyo O, Oladele RO, Obiako RO, Warris A, Akanmu SA (2019). Cryptococcal meningitis after ART: Need for proper baseline evaluation in the era of 'Test & Treat'. Med Mycol Case Rep, 24, 58-60.
Cryptococcal meningitis after ART: Need for proper baseline evaluation in the era of 'Test & Treat'.
Cryptococcal meningitis (CM) contributes significantly to high early mortality in the setting of advanced HIV. In resource poor settings, the current HIV disease management approach is focused on commencing antiretroviral therapy (ART) on the same day of HIV diagnosis ('Test and Treat'). The HIV program in Nigeria does not currently provide CrAg screening for patients with newly diagnosed and advanced HIV disease. We report a case of severe cryptococcal meningitis presenting following the commencement of ART. There is clear benefit in the early commencement of ART among HIV infected patients and to prevent patients lost to follow-up as aimed with the 'Test & Treat' approach. However, this approach needs to be balanced against the risk of IRIS and its associated morbidity and mortality when those patients are not being properly evaluated for opportunistic infections being present without overt symptoms.
Warris A, Lehrnbecher T, Roilides E, Castagnola E, Brüggemann RJM, Groll AH (2019). ESCMID-ECMM guideline: diagnosis and management of invasive aspergillosis in neonates and children. Clin Microbiol Infect, 25(9), 1096-1113.
ESCMID-ECMM guideline: diagnosis and management of invasive aspergillosis in neonates and children.
SCOPE: Presenting symptoms, distributions and patterns of diseases and vulnerability to invasive aspergillosis (IA) are similar between children and adults. However, differences exist in the epidemiology and underlying conditions, the usefulness of newer diagnostic tools, the pharmacology of antifungal agents and in the evidence from interventional phase 3 clinical trials. Therefore, the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM) have developed a paediatric-specific guideline for the diagnosis and management of IA in neonates and children. METHODS: Review and discussion of the scientific literature and grading of the available quality of evidence was performed by the paediatric subgroup of the ESCMID-ECMM-European Respiratory Society (ERS) Aspergillus disease guideline working group, which was assigned the mandate for the development of neonatal- and paediatric-specific recommendations. QUESTIONS: Questions addressed by the guideline included the epidemiology of IA in neonates and children; which paediatric patients may benefit from antifungal prophylaxis; how to diagnose IA in neonates and children; which antifungal agents are available for use in neonates and children; which antifungal agents are suitable for prophylaxis and treatment of IA in neonates and children; what is the role of therapeutic drug monitoring of azole antifungals; and which management strategies are suitable to be used in paediatric patients. This guideline provides recommendations for the diagnosis, prevention and treatment of IA in the paediatric population, including neonates. The aim of this guideline is to facilitate optimal management of neonates and children at risk for or diagnosed with IA.
Warris A (2019). Immunopathology of Aspergillus Infections in Children with Chronic Granulomatous Disease and Cystic Fibrosis. Pediatr Infect Dis J, 38(5), e96-e98. Author URL.
Lempers VJ, Meuwese E, Mavinkurve-Groothuis AM, Henriet S, van der Sluis IM, Hanff LM, Warris A, Koch BCP, Brüggemann RJ (2019). Impact of dose adaptations following voriconazole therapeutic drug monitoring in pediatric patients. Med Mycol, 57(8), 937-943.
Impact of dose adaptations following voriconazole therapeutic drug monitoring in pediatric patients.
Voriconazole is the mainstay of treatment for invasive aspergillosis in immunocompromised pediatric patients. Although Therapeutic Drug Monitoring (TDM) of voriconazole is recommended, it remains unknown if TDM-based dose adaptations result in target attainment. Patients 6 mg/l). Patient demographics, clinical characteristics, treatment, voriconazole dosing information, voriconazole Cmin before and after adjustment based on TDM were obtained. Twenty-one patients, median (range) age 7.0 (1.2-18.5) years, were identified in two centers. First Cmin (3.1 mg/l [0.1-13.5]) was obtained after 3 days (1-27) of treatment. The median of all Cmin (n = 485, median 11 per patient) was 2.16 mg/l (0.0 (undetectable)-28.0), with 24.1% of Cmin < 1 mg/l, 48.9% 1-4 mg/l, 9.3% 4-6 mg/l, and 17.7% > 6 mg/l. Intrapatient variability was large (94.1% for IV, 88.5% for PO). Dose increases at Cmin < 1 mg/l resulted in an increased Cmin in 76.4%, with 60% between 1 and 4 mg/l. Dose decreases at Cmin > 6 mg/l resulted in a decreased Cmin in 80%, with 51% between 1 and 4 mg/l. Overall, in 45% of the cases (33 out of 55 and 12 out of 45) therapeutic targets were attained after dose adjustment. Fifty-five percent of initial Cmin was outside the therapeutic target of 1-4 mg/l, with multiple dose adaptations required to achieve therapeutic concentrations. Only 60% and 51% of dose adaptations following sub- and supra-therapeutic Cmin, respectively, did result in target attainment. Intensive and continuous TDM of voriconazole is a prerequisite for ensuring adequate exposure in pediatric patients.
Ferreras-Antolín L, Sharland M, Warris A (2019). Management of Invasive Fungal Disease in Neonates and Children. Pediatr Infect Dis J, 38(6S Suppl 1), S2-S6.
Management of Invasive Fungal Disease in Neonates and Children.
Invasive fungal diseases (IFD) are an important cause of morbidity and mortality in premature neonates and immunocompromised pediatric patients. Their diagnostic and therapeutic management remains a challenge. A nationwide survey was conducted among 13 of the largest pediatric units in the United Kingdom, to obtain insight in the current management of IFD in neonates and children. All responding centers were tertiary teaching centers. The use of fungal diagnostic tools and imaging modalities varied among centers. Antifungal prophylaxis was prescribed in most centers for extreme-low birth weight (LBW) infants and high-risk hemato-oncologic patients, but with a huge variety in antifungals given. An empirical treatment was favored by most centers in case of febrile neutropenia. First line therapy for candidemia consists of either fluconazole or liposomal amphotericin B, with voriconazole being first-line therapy for invasive aspergillosis. Disseminated invasive aspergillosis was most often mentioned as a reason to prescribe combination antifungal therapy. In conclusion, this survey reinforces the fact that there are still important aspects in the management of pediatric IFD which should ideally be addressed in pediatric clinical trials. Attention needs to be given the knowledge gaps as observed in the results of our survey to optimize the management of IFD in children and neonates.
Brown AJP, Gow NAR, Warris A, Brown GD (2019). Memory in Fungal Pathogens Promotes Immune Evasion, Colonisation, and Infection. Trends in Microbiology, 27(3), 219-230.
Memory in Fungal Pathogens Promotes Immune Evasion, Colonisation, and Infection
By analogy with Pavlov's dogs, certain pathogens have evolved anticipatory behaviours that exploit specific signals in the human host to prepare themselves against imminent host challenges. This adaptive prediction, a type of history-dependent microbial behaviour, represents a primitive form of microbial memory. For fungal pathogens, adaptive prediction helps them circumvent nutritional immunity, protects them against phagocytic killing, and activates immune evasion strategies. We describe how these anticipatory responses, and the contrasting lifestyles and evolutionary trajectories of fungal pathogens, have influenced the evolution of such adaptive behaviours, and how these behaviours affect host colonisation and infection.
Ferreras-Antolín L, Irwin A, Atra A, Dermirjian A, Drysdale SB, Emonts M, McMaster P, Paulus S, Patel S, Kinsey S, et al (2019). Neonatal Antifungal Consumption is Dominated by Prophylactic Use; Outcomes from the Pediatric Antifungal Stewardship: Optimizing Antifungal Prescription Study. Pediatr Infect Dis J, 38(12), 1219-1223.
Neonatal Antifungal Consumption is Dominated by Prophylactic Use; Outcomes from the Pediatric Antifungal Stewardship: Optimizing Antifungal Prescription Study.
BACKGROUND: Diagnostic challenges combined with the vulnerability of neonates to develop invasive candidiasis (IC) may lead to antifungal administration in the absence of IC. A modified point-prevalence study was performed to obtain an improved insight and understanding of antifungal prescribing in this specific patient population. METHODS: Neonates and infants ≤90 days of age receiving systemic antifungals from 12 centers in England were included. Data were collected prospectively during 26 consecutive weeks and entered into an online REDCap database. RESULTS: Two hundred eighty neonates and infants were included, the majority ≤1 month of age (68.2%). Prematurity was the commonest underlying condition (68.9%). Antifungals were prescribed for prophylactic reason in 79.6%; of those, 64.6% and 76.3% were extreme low birth weight infants and prematurely born neonates, respectively. Additional risk factors were present in almost all patients, but only 44.7% had ≥3 risk factors rendering them more susceptible to develop IC. Nonpremature and non extremely low birth weight premature infants only scored ≥3 risk factors in 32.6% and 15%, respectively. Fluconazole was the most common antifungal used (76.7% of all prescriptions), and commonly underdosed as treatment. The number of microbiologic proven IC was low, 5.4%. CONCLUSIONS: Neonatal antifungal prophylaxis is commonly prescribed outside the recommendations based on known risk profiles. Fluconazole is the main antifungal prescribed in neonates and infants, with underdosing frequently observed when prescribed for treatment. Number of proven IC was very low. These observations should be taken into consideration to develop a national pediatric Antifungal Stewardship program aiming to guide rational prescribing.
Warris A, Ballou ER (2019). Oxidative responses and fungal infection biology. Seminars in Cell and Developmental Biology, 89, 34-46.
Oxidative responses and fungal infection biology
The balance between reactive oxygen species and reactive nitrogen species production by the host and stress response by fungi is a key axis of the host-pathogen interaction. This review will describe emerging themes in fungal pathogenesis underpinning this axis.
Ballard E, Zoll J, Melchers WJG, Brown AJP, Warris A, Verweij PE (2019). Raw genome sequence data for 13 isogenic Aspergillus fumigatus strains isolated over a 2 year period from a patient with chronic granulomatous disease. Data Brief, 25
Raw genome sequence data for 13 isogenic Aspergillus fumigatus strains isolated over a 2 year period from a patient with chronic granulomatous disease.
Azole-resistance in Aspergillus fumigatus is an emerging worldwide threat as it precludes the use of one of the 3 major classes of antifungal drugs to treat chronic and invasive aspergillosis [1]. In addition to the well-known environmental emergence of azole-resistant A. fumigatus strains, associated with the use of fungicides in agriculture [2], [3], the development of in-host resistance, facilitated by medical antifungal use, has been described [4]. Investigations involving linked sets of (isogenic) clinical isolates of A. fumigatus sequentially recovered from individual patients, are extremely important in order to improve our understanding of how azole resistance develops in-host. Here we present the whole genome sequences of 13 clinical isogenic A. fumigatus isolates. These isolates were cultured from a single patient suffering from invasive aspergillosis over a period of 2 years. This patient underwent a wide range of antifungal therapies and the resultant isolates acquired multiple azole resistance in-host during the course of infection. The data presented here is related to our research paper titled "In-host microevolution of Aspergillus fumigatus: a phenotypic and genotypic analysis" which describes the phenotypic characterisation of these clinical isolates [5]. The raw sequence data was deposited in the NCBI Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra), under BioProject ID number PRJNA528395.
Ballard E, Weber J, Melchers WJG, Tammireddy S, Whitfield PD, Brakhage AA, Brown AJP, Verweij PE, Warris A (2019). Recreation of in-host acquired single nucleotide polymorphisms by CRISPR-Cas9 reveals an uncharacterised gene playing a role in Aspergillus fumigatus azole resistance via a non-cyp51A mediated resistance mechanism. Fungal Genet Biol, 130, 98-106.
Recreation of in-host acquired single nucleotide polymorphisms by CRISPR-Cas9 reveals an uncharacterised gene playing a role in Aspergillus fumigatus azole resistance via a non-cyp51A mediated resistance mechanism.
The human host comprises a range of specific niche environments. In order to successfully persist, pathogens such as Aspergillus fumigatus must adapt to these environments. One key example of in-host adaptation is the development of resistance to azole antifungals. Azole resistance in A. fumigatus is increasingly reported worldwide and the most commonly reported mechanisms are cyp51A mediated. Using a unique series of A. fumigatus isolates, obtained from a patient suffering from persistent and recurrent invasive aspergillosis over 2 years, this study aimed to gain insight into the genetic basis of in-host adaptation. Single nucleotide polymorphisms (SNPs) unique to a single isolate in this series, which had developed multi-azole resistance in-host, were identified. Two nonsense SNPs were recreated using CRISPR-Cas9; these were 213. in svf1 and 167. in uncharacterised gene AFUA_7G01960. Phenotypic analyses including antifungal susceptibility testing, mycelial growth rate assessment, lipidomics analysis and statin susceptibility testing were performed to associate genotypes to phenotypes. This revealed a role for svf1 in A. fumigatus oxidative stress sensitivity. In contrast, recapitulation of 167. in AFUA_7G01960 resulted in increased itraconazole resistance. Comprehensive lipidomics analysis revealed decreased ergosterol levels in strains containing this SNP, providing insight to the observed itraconazole resistance. Decreases in ergosterol levels were reflected in increased resistance to lovastatin and nystatin. Importantly, this study has identified a SNP in an uncharacterised gene playing a role in azole resistance via a non-cyp51A mediated resistance mechanism. This mechanism is of clinical importance, as this SNP was identified in a clinical isolate, which acquired azole resistance in-host.
Brunel SF, Willment JA, Brown GD, Devereux G, Warris A (2018). Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity. ERS Monograph, 4(2).
Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity
© ERS 2018. Aspergillus fumigatus infects up to 50% of cystic fibrosis (CF) patients and may play a role in progressive lung disease. As cystic fibrosis transmembrane conductance regulator is expressed in cells of the innate immune system, we hypothesised that impaired antifungal immune responses play a role in CF-related Aspergillus lung disease. Peripheral blood mononuclear cells, polymorphonuclear cells (PMN) and monocytes were isolated from blood samples taken from CF patients and healthy volunteers. Live-cell imaging and colorimetric assays were used to assess antifungal activity in vitro. Production of reactive oxygen species (ROS) was measured using luminol-induced chemiluminescence and was related to clinical metrics as collected by case report forms. CF phagocytes are as effective as those from healthy controls with regards to phagocytosis, killing and restricting germination of A. fumigatus conidia. ROS production by CF phagocytes was up to four-fold greater than healthy controls (p
Warris A (2018). Candida auris, what do paediatricians need to know?. Archives of Disease in Childhood, 103(9), 891-894.
Candida auris, what do paediatricians need to know?
The newly recognised and emerging fungal species, Candida auris, has caused worldwide invasive infections and has been implicated in difficult to control hospital outbreaks. Challenges are encountered in the correct identification of this fungus as commonly used phenotypic and biochemical methods fail to differentiate C. auris from other Candida species. Its resistance profile, over 90% of isolates are fluconazole resistant and 35% are resistant to amphotericin, confronts clinicians with the restricted arsenal of antifungals and concerns about optimal treatment. The very first C. auris isolate was recovered from a paediatric patient in retrospect. Although infections with the more antifungal-resistant Candida species are less frequently observed in paediatric patients, this seems to be different for C. auris infections.
Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, Lass-Flörl C, Lewis RE, Munoz P, Verweij PE, et al (2018). Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clinical Microbiology and Infection, 24, e1-e38.
Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline
The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.
Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D (2018). Ibrutinib blocks Btk-dependent NF-ĸB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Blood, 132(18), 1985-1988.
Ballard E, Melchers WJG, Zoll J, Brown AJP, Verweij PE, Warris A (2018). In-host microevolution of Aspergillus fumigatus: a phenotypic and genotypic analysis. Fungal Genetics and Biology, 113, 1-13.
In-host microevolution of Aspergillus fumigatus: a phenotypic and genotypic analysis
In order to survive, Aspergillus fumigatus must adapt to specific niche environments. Adaptation to the human host includes modifications facilitating persistent colonisation and the development of azole resistance. The aim of this study is to advance understanding of the genetic and physiological adaptation of A. fumigatus in patients during infection and treatment. Thirteen A. fumigatus strains were isolated from a single chronic granulomatous disease patient suffering from persistent and recurrent invasive aspergillosis over a period of 2 years. All strains had identical microsatellite genotypes and were considered isogenic. Whole genome comparisons identified 248 non-synonymous single nucleotide polymorphisms. These non-synonymous mutations have potential to play a role in in-host adaptation. The first 2 strains isolated were azole susceptible, whereas later isolates were itraconazole, voriconazole and/or posaconazole resistant. Growth assays in the presence and absence of various antifungal stressors highlighted minor changes in growth rate and stress resistance, with exception of one isolate showing a significant growth defect. Poor conidiation was observed in later isolates. In certain drug resistant isolates conidiation was restored in the presence of itraconazole. Differences in virulence were observed as demonstrated in a Galleria mellonella infection model. We conclude that the microevolution of A. fumigatus in this patient has driven the emergence of both Cyp51A-independent and Cyp51A-dependent, azole resistance mechanisms, and additional phenotypes that are likely to have promoted fungal persistence.
Van Dijck P, Sjollema J, Cammue BP, Lagrou K, Berman J, d'Enfert C, Andes DR, Arendrup MC, Brakhage AA, Calderone R, et al (2018). Methodologies for in vitro and in vivo evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms. Microb Cell, 5(7), 300-326.
Methodologies for in vitro and in vivo evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms.
Unlike superficial fungal infections of the skin and nails, which are the most common fungal diseases in humans, invasive fungal infections carry high morbidity and mortality, particularly those associated with biofilm formation on indwelling medical devices. Therapeutic management of these complex diseases is often complicated by the rise in resistance to the commonly used antifungal agents. Therefore, the availability of accurate susceptibility testing methods for determining antifungal resistance, as well as discovery of novel antifungal and antibiofilm agents, are key priorities in medical mycology research. To direct advancements in this field, here we present an overview of the methods currently available for determining (i) the susceptibility or resistance of fungal isolates or biofilms to antifungal or antibiofilm compounds and compound combinations; (ii) the in vivo efficacy of antifungal and antibiofilm compounds and compound combinations; and (iii) the in vitro and in vivo performance of anti-infective coatings and materials to prevent fungal biofilm-based infections.
An SQ, Warris A, Turner S (2018). Microbiome characteristics of induced sputum compared to bronchial fluid and upper airway samples. Pediatric Pulmonology, 53(7), 921-928.
Microbiome characteristics of induced sputum compared to bronchial fluid and upper airway samples
Objective: the study of the community of microorganisms (the microbiota) in the lower airways in children is restricted to opportunistic sampling in children undergoing elective general anaesthetic. Here we tested the hypothesis that induced sputum is a valid alternative to directly sampling the lower airways to study lower airway microbiota. Methods: Children scheduled for elective operations were recruited. Pre-operatively a sample of induced sputum was obtained. After anaesthesia was induced, a bronchial brushing and swabs of the upper respiratory tract were obtained. Bacterial community analysis was performed by amplification of the V3–V4 16S rRNA gene region. Results: Twenty children were recruited, mean age 10.7 years. Induced sputum samples were obtained from 12 children, bronchial brushing from 14 and nasal, mouth, and throat samples in 15, 16, and 17 children. The profile of bacterial communities was similar in the mouth, throat, and sputum samples with the nose and bronchial samples being different. Actinobacteria species dominated the nose and mouth, Fusobacteria were the dominant species in the throat and sputum while Proteobacteria species dominated in bronchial samples. Forty-one percent of detected bacteria in bronchial samples were unclassified. Bacterial communities from the mouth, throat, and induced sputum were tightly clustered and were distinct from nose and those found in bronchial communities. Conclusions: Induced sputum may not be a valid surrogate for microbiome assessment of the lower airways in all individuals. Many bacteria in bronchial samples were not recognized by standard testing, suggesting that our understanding of the lower airway microbiota in children remains rudimentary.
Warris A (2018). Special issue: Host–fungus interactions. Journal of Fungi, 4(1).
Gow NAR, Amin T, McArdle K, Brown AJP, Brown GD, Warris A, the WTSA-MMFI Consortium (2018). Strategic Research Funding: a Success Story for Medical Mycology. Trends in Microbiology, 26(10), 811-813.
Strategic Research Funding: a Success Story for Medical Mycology
The Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology is a unique investment that aimed to bolster capacity, training and research activity throughout the UK. This article summarises the rationale for collective collaboration of multiple institutions to achieve synergies and address a common medical problem.
Seyedmousavi S, van der Lee HA, Verweij PE, Warris A (2017). Absent in vitro interaction between chloroquine and antifungals against Aspergillus fumigatus. Clinical Microbiology and Infection, 23(9), 679-681.
Pana ZD, Roilides E, Warris A, Groll AH, Zaoutis T (2017). Epidemiology of Invasive Fungal Disease in Children. Journal of the Pediatric Infectious Diseases Society, 6(1), S3-S11.
Epidemiology of Invasive Fungal Disease in Children
Considerable progress has been made in the prevention, diagnosis, and management of pediatric patients with invasive fungal disease (IFD). The reported decreasing trend in the incidence of invasive candidiasis (IC) over the past 15 years in both neonates and children has been encouraging. Nevertheless, due to the growing number of immunocompromised children at risk for IFD, this disease continues to be associated with significant morbidity and death and with increased financial burden to the health care system. Therefore, it is important to understand the contemporary epidemiology of IFD. Incidence rates of IFD in children are affected by geographical, population, and time variability. There is an ongoing effort to constantly document and update the incidence of IFD and species distribution among different pediatric populations as a means to direct preventative, diagnostic, and therapeutic resources to the most appropriate subset of patients. Children with a hematologic malignancy or a primary or secondary immunodeficiency, those undergoing solid organ or hematopoietic stem cell transplantation, and premature neonates are the major subsets of pediatric patients at risk of developing IFD. In this review, we focus on fungal disease epidemiology with a specific emphasis on the 2 most common pediatric IFDs, IC and invasive aspergillosis (IA).
Bastiaans DET, Immohr LI, Zeinstra GG, Strik-Albers R, Pein-Hackelbusch M, van der Flier M, de Haan AFJ, Boelens JJ, Lankester AC, Burger DM, et al (2017). In vivo and in vitro palatability testing of a new paediatric formulation of valaciclovir. British Journal of Clinical Pharmacology, 83(12), 2789-2797.
In vivo and in vitro palatability testing of a new paediatric formulation of valaciclovir
Aims: the palatability of a new paediatric formulation of valaciclovir was assessed in children and their parents: non-inferiority of the new paediatric formulation (test formulation) compared to the reference formulation was investigated. Methods: in vivo palatability testing was performed in a randomized, two-period, multicentre, cross-over study. Children and their parents scored the liking of the new paediatric valaciclovir formulation and the reference formulation on a 100 mm visual analogue scale (VAS). To support formulation development and palatability testing, electronic tongue measurements were applied. Results: the electronic tongue measurement indicated taste-masking capabilities for three different formulations in the developmental phase. A glycerol-based formulation was further tested and compared to the reference formulation prepared out of crushed and suspended tablets. The mean difference (95% CI) in VAS scores between both formulations, as indicated by the children (n = 20), was 2.4 (−8.5, 13) mm, in favour of the new paediatric valaciclovir formulation. The mean (95% CI) difference in VAS scores indicated by the parents (n = 20) was −0.9 (−12, 9.8) mm. Conclusion: the palatability of the new paediatric valaciclovir formulation was considered non-inferior to the reference formulation prepared out of crushed tablets. We were able to optimize the study design and number of children to be included in the palatability testing by using electronic tongue measurements.
Brunel SF, Bain JM, King J, Heung LJ, Kasahara S, Hohl TM, Warris A (2017). Live imaging of antifungal activity by human primary neutrophils and monocytes in response to A. fumigatus. Journal of Visualized Experiments, 2017(122).
Live imaging of antifungal activity by human primary neutrophils and monocytes in response to A. fumigatus
Aspergillus fumigatus is an opportunistic fungal pathogen causing invasive infections in immunocompromised hosts with a high case-fatality rate. Research investigating immunological responses against A. fumigatus has been limited by the lack of consistent and reliable assays for measuring the antifungal activity of specific immune cells in vitro. A new method is described to assess the antifungal activity of primary monocytes and neutrophils from human donors against A. fumigatus using FLuorescent Aspergillus REporter (FLARE) conidia. These conidia contain a genetically encoded dsRed reporter, which is constitutively expressed by live FLARE conidia, and are externally labeled with Alexa Fluor 633, which is resistant to degradation within the phagolysosome, thus allowing a distinction between live and dead A. fumigatus conidia. Video microscopy and flow cytometry are subsequently used to visualize the interaction between conidia and innate immune cells, assessing fungicidal activity whilst also providing a wealth of information on phagocyte migration, phagocytosis and the inhibition of fungal growth. This novel technique has already provided exciting new insights into the host-pathogen interaction of primary immune cells against A. fumigatus. It is important to note the laboratory setup required to perform this assay, including the necessary microscopy and flow cytometry facilities, and the capacity to work with human donor blood and genetically manipulated fungi. However, this assay is capable of generating large amounts of data and can reveal detailed insights into the antifungal response. This protocol has successfully been used to study the host-pathogen interaction of primary immune cells against A. fumigatus. It is important to note the laboratory setup required to perform this assay, including the necessary microscopy and flow cytometry facilities, and the capacity to work with human donor blood and genetically manipulated fungi. However, this assay is capable of generating large amounts of data and can reveal detailed insights into the antifungal response. This protocol has successfully been used to study the host-pathogen interaction of primary immune cells against A. fumigatus.
Naselli A, Bishop H, Walker S, Warris A (2017). Neutropenic acute acalculous cholecystitis (AAC) in a 12-year-old boy with T-acute lymphoblastic leukemia successfully managed with conservative treatment. Pediatric Hematology and Oncology, 34(1), 24-28.
Neutropenic acute acalculous cholecystitis (AAC) in a 12-year-old boy with T-acute lymphoblastic leukemia successfully managed with conservative treatment
Acute acalculous cholecystitis (AAC) is an inflammation of the gallbladder without the presence of gallstones. In children with malignancies or chemotherapy-induced neutropenia, AAC is very rare. Clinical diagnosis of AAC remains difficult in this patient population but an early recognition followed by an appropriate intervention may confer a benefit. Only three pediatric patients with underlying hematological malignancies whose clinical treatment course was complicated by the development of AAC have been described. We describe a neutropenic pediatric patient who developed AAC following chemotherapy for acute T-cell acute lymphoblastic leukemia (T-ALL), which was successfully managed with conservative treatment. Abbreviations: AAC: Acute acalculous cholecystitis; T-ALL: T-cell acute lymphoblastic leukemia; TPN: Total parenteral nutrition.
Curtis N, Pollard AJ, Finn A, Ramilo O, Dobson S, Warris A, van Rossum A (2017). Preface. Journal of Infection, 74
Warris A, Lehrnbecher T (2017). Progress in the Diagnosis of Invasive Fungal Disease in Children. Current Fungal Infection Reports, 11(2), 35-44.
Progress in the Diagnosis of Invasive Fungal Disease in Children
Purpose of Review: This review summarizes the fungal diagnostic measures currently available for use in paediatric patients at high risk for developing invasive fungal disease (IFD) and those suspected of having an IFD. The clinical utility of each test is described based on reported performances of individual tests in specific paediatric populations. Recent Findings: Available studies in the paediatric population are scarce and are characterized by a huge heterogeneity in underlying diseases (e.g. different risk for IFD), different study objectives and management strategies (screening versus diagnostic) used. Summary: a final valuation of paediatric studies on fungal diagnostic tools is limited. While the galactomannan and fungal PCR assays are useful to exclude the presence of IFD, it is unclear if mannan, mannan antibodies and β-D-glucan are of benefit due to a lack of studies or validation of the cut-off, respectively. Well-designed multicentre paediatric studies are urgently needed to improve the outcome of IFD.
King J, Pana ZD, Lehrnbecher T, Steinbach WJ, Warris A (2017). Recognition and Clinical Presentation of Invasive Fungal Disease in Neonates and Children. Journal of the Pediatric Infectious Diseases Society, 6(1), S12-S21.
Recognition and Clinical Presentation of Invasive Fungal Disease in Neonates and Children
Invasive fungal diseases (IFDs) are devastating opportunistic infections that result in significant morbidity and death in a broad range of pediatric patients, particularly those with a compromised immune system. Recognizing them can be difficult, because nonspecific clinical signs and symptoms or isolated fever are frequently the only presenting features. Therefore, a high index of clinical suspicion is necessary in patients at increased risk of IFD, which requires knowledge of the pediatric patient population at risk, additional predisposing factors within this population, and the clinical signs and symptoms of IFD. With this review, we aim to summarize current knowledge regarding the recognition and clinical presentation of IFD in neonates and children.
Calley JL, Warris A (2017). Recognition and diagnosis of invasive fungal infections in neonates. Journal of Infection, 74, S108-S113.
Recognition and diagnosis of invasive fungal infections in neonates
Fungal infections largely caused by Candida species are responsible for a significant disease burden in neonates and invasive candidiasis in hospitalised neonates has high associated morbidity and mortality. Early initiation of antifungal treatment improves outcome but the recognition and diagnosis of systemic fungal infection in this population is difficult due to the non-specific clinical presentation and the high false negative rate of cultures. There is a need for a practical, sensitive and rapid diagnostic test to enhance identification and early treatment. Serum detection of (1,3)-β-d-glucan and Candida PCR are promising candidates but at present limited data exists for their use in the neonatal intensive care setting. Until such investigations are validated, early initiation of antifungal treatment on the basis of risk factor profile and clinical features remains the safest practical approach.
Bastiaans DET, Bartels-Wilmer CM, Colbers APH, Heijens CAW, Velthoven-Graafland K, Smeets OSNM, Vink N, Harbers VEM, Warris A, Burger DM, et al (2016). A new paediatric formulation of valaciclovir: Development and bioequivalence assessment. Archives of Disease in Childhood, 101(10), 971-972.
King J, Henriet SSV, Warris A (2016). Aspergillosis in chronic granulomatous disease. Journal of Fungi, 2(2).
Aspergillosis in chronic granulomatous disease
Patients with chronic granulomatous disease (CGD) have the highest life-time incidence of invasive aspergillosis and despite the availability of antifungal prophylaxis, infections by Aspergillus species remain the single most common infectious cause of death in CGD. Recent developments in curative treatment options, such as haematopoietic stem cell transplantation, will change the prevalence of infectious complications including invasive aspergillosis in CGD patients. However, invasive aspergillosis in a previously healthy host is often the first presenting feature of this primary immunodeficiency. Recognizing the characteristic clinical presentation and understanding how to diagnose and treat invasive aspergillosis in CGD is of utmost relevance to improve clinical outcomes. Significant differences exist in fungal epidemiology, clinical signs and symptoms, and the usefulness of non-culture based diagnostic tools between the CGD host and neutropenic patients, reflecting underlying differences in the pathogenesis of invasive aspergillosis shaped by the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase deficiency.
King J, Brunel SF, Warris A (2016). Aspergillus infections in cystic fibrosis. Journal of Infection, 72, S50-S55.
Aspergillus infections in cystic fibrosis
Patients with cystic fibrosis (CF) suffer from chronic lung infection and airway inflammation. Respiratory failure secondary to chronic or recurrent infection remains the commonest cause of death and accounts for over 90% of mortality. Bacteria as Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia complex have been regarded the main CF pathogens and their role in progressive lung decline has been studied extensively. Little attention has been paid to the role of Aspergillus spp. and other filamentous fungi in the pathogenesis of non-ABPA (allergic bronchopulmonary aspergillosis) respiratory disease in CF, despite their frequent recovery in respiratory samples. It has become more apparent however, that Aspergillus spp. may play an important role in chronic lung disease in CF. Research delineating the underlying mechanisms of Aspergillus persistence and infection in the CF lung and its link to lung deterioration is lacking. This review summarizes the Aspergillus disease phenotypes observed in CF, discusses the role of CFTR (cystic fibrosis transmembrane conductance regulator)-protein in innate immune responses and new treatment modalities.
Tak R, Semmekrot B, Warris A, Yntema JB, Stelma F, Neeleman C (2016). Bacterial Tracheitis and Septic Shock. Pediatric Infectious Disease Journal, 35(2), 226-227.
Henriet SSV, Van De Sande WWJ, Lee MJ, Simonetti E, Momany M, Verweij PE, Rijs AJMM, Ferwerda G, Sheppard DC, De Jonge MI, et al (2016). Decreased Cell Wall Galactosaminogalactan in Aspergillus nidulans Mediates Dysregulated Inflammation in the Chronic Granulomatous Disease Host. Journal of Interferon and Cytokine Research, 36(8), 488-498.
Decreased Cell Wall Galactosaminogalactan in Aspergillus nidulans Mediates Dysregulated Inflammation in the Chronic Granulomatous Disease Host
Invasive aspergillosis is a major threat to patients suffering from impaired neutrophil function, with Aspergillus fumigatus being the most common species causing this life-threatening condition. Patients with chronic granulomatous disease (CGD) not only develop infections with A. fumigatus, but also exhibit a unique susceptibility to infection with the normally nonpathogenic species Aspergillus nidulans. In this study, we compared the inflammatory cytokine response of peripheral blood mononuclear cells (PBMCs) from healthy and CGD patients to these two fungal species. CGD patients displayed evidence for a chronic hyperinflammatory state as indicated by elevated plasma IL-1β and TNF-α levels. PBMCs isolated from CGD patients secreted higher levels of IL-1β and TNF-α in response to A. nidulans as compared with A. fumigatus. The presence or absence of melanin in the cell wall of A. nidulans did not alter the cytokine release by healthy or CGD PBMCs. In contrast, A. fumigatus mutants lacking melanin stimulated higher levels of proinflammatory cytokine release from healthy, but not CGD PBMCs. Purified cell wall polysaccharides of A. nidulans induced a much higher level of IL-1β secretion by CGD PBMCs than did cell wall polysaccharides isolated from A. fumigatus. Using modified A. nidulans strains overexpressing galactosaminogalactan, we were able to show that the increased secretion of inflammatory cytokines by CGD PBMCs in response to A. nidulans are a consequence of low levels of cell wall-associated galactosaminogalactan in this species.
Murray JE, Bicknell LS, Yigit G, Duker AL, van Kogelenberg M, Haghayegh S, Wieczorek D, Kayserili H, Albert MH, Wise CA, et al (2016). Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency (vol 35, pg 76, 2014). HUMAN MUTATION, 37(9), 983-983. Author URL.
Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, Ouachee-Chardin M, Fouyssac F, Girisha KM, Etzioni A, et al (2016). Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. BLOOD, 127(25), 3154-3164. Author URL.
Warris A (2016). Prophylactic antibiotics should be used in children with repaired oesophageal atresia and tracheo-oesophageal fistula: the case against. Paediatric Respiratory Reviews, 18, 62-63.
Bielicki JA, Sharland M, Johnson AP, Henderson KL, Cromwell DA, Berger C, Esposito S, Danieli E, Tenconi R, Folgori L, et al (2016). Selecting appropriate empirical antibiotic regimens for paediatric bloodstream infections: Application of a Bayesian decision model to local and pooled antimicrobial resistance surveillance data. Journal of Antimicrobial Chemotherapy, 71(3), 794-802.
Selecting appropriate empirical antibiotic regimens for paediatric bloodstream infections: Application of a Bayesian decision model to local and pooled antimicrobial resistance surveillance data
Objectives: the objective of this study was to evaluate the ability of weighted-incidence syndromic combination antibiograms (WISCAs) to inform the selection of empirical antibiotic regimens for suspected paediatric bloodstream infections (BSIs) by comparing WISCAs derived using data from single hospitals and from a multicentre surveillance dataset. Methods: WISCAs were developed by estimating the coverage of five empirical antibiotic regimens for childhood BSI using a Bayesian decision tree. The study used microbiological data on ~2000 bloodstream isolates collected over 2 years from 19 European hospitals. We evaluated the ability of a WISCA to show differences in regimen coverage at two exemplar hospitals. For each, a WISCA was first calculated using only their local data; a second WISCA was calculated using pooled data from all 19 hospitals. Results: the estimated coverage of the five regimens was 72%-86% for Hospital 1 and 79%-94% for Hospital 2, based on their own data. In both cases, the best regimens could not be definitively identified because the differences in coverage were not statistically significant. For Hospital 1, coverage estimates derived using pooled data gave sufficient precision to reveal clinically important differences among regimens, including high coverage provided by a narrow-spectrum antibiotic combination. For Hospital 2, the hospital and pooled data showed signs of heterogeneity and the use of pooled data was judged not to be appropriate. Conclusions: the Bayesian WISCA provides a useful approach to pooling information from different sources to guide empirical therapy and could increase confidence in the selection of narrow-spectrum regimens.
Bart IY, Mourits M, van Gent R, van Leuken MH, Hilbink M, Warris A, Wever PC, de Vries E (2016). Sputum Induction in Children is Feasible and Useful in a Bustling General Hospital Practice. Glob Pediatr Health, 3
Sputum Induction in Children is Feasible and Useful in a Bustling General Hospital Practice.
We prospectively studied the feasibility and effectiveness of sputum induction in obtaining good quality sputum and its subsequent bacterial yield in children with clinically suspected acute lower-respiratory-tract infection (aLRTI). Good quality sputum was collected in 89/98 (91%) patients. Sputum cultures revealed ≥1 bacterial pathogens in 22 cases (25%). Adverse events were infrequent and mild (6%). Sputum induction is feasible in young children and leads to an increased number of etiological diagnoses of aLRTI.
Warris A (2016). The European Paediatric Mycology Network (EPMyN): Towards a Better Understanding and Management of Fungal Infections in Children. Current Fungal Infection Reports, 10(1), 7-9.
The European Paediatric Mycology Network (EPMyN): Towards a Better Understanding and Management of Fungal Infections in Children
The European Paediatric Mycology Network (EPMyN) was launched in 2014 to create a European platform for research and education in the field of paediatric mycology. The EPMyN aims to address the lack of paediatric specific evidence and knowledge needed to (1) improve the management and outcome of invasive fungal infections in children and neonates and to (2) enhance and develop paediatric antifungal stewardship programmes.
Agrawal S, Barnes R, Brüggemann RJ, Rautemaa-Richardson R, Warris A (2016). The role of the multidisciplinary team in antifungal stewardship. Journal of Antimicrobial Chemotherapy, 71, ii37-ii42.
The role of the multidisciplinary team in antifungal stewardship
There are a variety of challenges faced in the management of invasive fungal diseases (IFD), including high case-fatality rates, high cost of antifungal drugs and development of antifungal resistance. The diagnostic challenges and poor outcomes associated with IFD have resulted in excessive empirical use of antifungals in various hospital settings, exposing many patients without IFD to potential drug toxicities as well as causing spiralling antifungal drug costs. Further complexity arises as different patient groups show marked variation in their risk for IFD, fungal epidemiology, sensitivity and specificity of diagnostic tests and the pharmacokinetics and pharmacodynamics of antifungal drugs. To address these issues and to ensure optimal management of IFD, specialist knowledge and experience from a range of backgrounds is required, which extends beyond the remit of most antibiotic stewardship programmes. The first step in the development of any antifungal stewardship (AFS) programme is to build a multidisciplinary team encompassing the necessary expertise in the management of IFD to develop and implement the AFS programme. The specific roles of the key individuals within the AFS team and the importance of collaboration are discussed in this article.
Rokx C, Gras L, van de Vijver DAMC, Verbon A, Rijnders BJA, Prins JM, Kuijpers TW, Scherpbier HJ, van der Meer JTM, Wit FWMN, et al (2016). Virological responses to lamivudine or emtricitabine when combined with tenofovir and a protease inhibitor in treatment-naïve HIV-1-infected patients in the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. HIV Medicine, 17(8), 571-580.
Virological responses to lamivudine or emtricitabine when combined with tenofovir and a protease inhibitor in treatment-naïve HIV-1-infected patients in the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort
Objectives: Lamivudine (3TC) and emtricitabine (FTC) are considered interchangeable in recommended tenofovir disoproxil-fumarate (TDF)-containing combination antiretroviral therapies (cARTs). This statement of equivalence has not been systematically studied. We compared the treatment responses to 3TC and FTC combined with TDF in boosted protease inhibitor (PI)-based cART for HIV-1-infected patients. Methods: an observational study in the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort was carried out between 2002 and 2013. Virological failure rates, time to HIV RNA suppression < 400 copies/mL, and time to treatment failure were analysed using multivariable logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score-adjusted models. Results: a total of 1582 ART-naïve HIV-1-infected patients initiated 3TC or FTC with TDF and ritonavir-boosted darunavir (29.6%), atazanavir (41.5%), lopinavir (27.1%) or another PI (1.8%). Week 48 virological failure rates on 3TC and FTC were comparable (8.9% and 5.6%, respectively; P = 0.208). The multivariable adjusted odds ratio of virological failure when using 3TC instead of FTC with TDF in PI-based cART was 0.75 [95% confidence interval (CI) 0.32–1.79; P = 0.51]. Propensity score-adjusted models showed comparable results. The adjusted hazard ratio (HR) for treatment failure of 3TC compared with FTC was 1.15 (95% CI 0.58–2.27) within 240 weeks after cART initiation. The time to two consecutive HIV RNA measurements < 400 copies/mL within 48 weeks (HR 0.94; 95% CI 0.78–1.16) and the time to treatment failure after suppression < 400 copies/mL (HR 0.94; 95% CI 0.36–2.50) were not significantly influenced by the use of 3TC in TDF/PI-containing cART. Conclusions: the virological responses were not significantly different in treatment-naïve HIV-1-infected patients starting either 3TC/TDF or FTC/TDF and a ritonavir-boosted PI.
Bielicki JA, Lundin R, Sharland M (2015). Antibiotic Resistance Prevalence in Routine Bloodstream Isolates from Children's Hospitals Varies Substantially from Adult Surveillance Data in Europe. Pediatric Infectious Disease Journal, 34(7), 734-741.
Bhatt JM, Bush A, van Gerven M, Nissenkorn A, Renke M, Yarlett L, Taylor M, Tonia T, Warris A, Zielen S, et al (2015). Ataxia telangiectasia: why should the ERS care?. Eur Respir J, 46(6), 1557-1560. Author URL.
Warris A (2015). Azole-resistant aspergillosis. Journal of Infection, 71(S1), S121-S125.
Azole-resistant aspergillosis
Azole-resistance in Aspergillus fumigatus is emerging and is becoming an increasing problem in the management of aspergillosis. Two types of development of resistance have been described; resistance acquired during azole treatment in an individual patient and through environmental exposure to fungicides. The main molecular mechanism of azole resistance in A. fumigatus is explained by mutations in the cyp51A-gene. The environmental route of resistance development is particularly worrying and may affect all patients whether azole exposed or naïve, and whether suffering from acute or chronic aspergillosis. No management guidelines to assist clinicians confronted with azole-resistant aspergillosis are available and pre-clinical and clinical evidence supporting treatment choices is scarce.
(2015). Boosted Lopinavir– Versus Boosted Atazanavir–Containing Regimens and Immunologic, Virologic, and Clinical Outcomes: a Prospective Study of HIV-Infected Individuals in High-Income Countries. Clinical Infectious Diseases, 60(8), 1262-1268.
Bruyand M, Ryom L, Shepherd L, Fatkenheuer G, Grulich A, Reiss P, de Wit S, d´Arminio Monforte A, Furrer H, Pradier C, et al (2015). Cancer Risk and Use of Protease Inhibitor or Nonnucleoside Reverse Transcriptase Inhibitor–Based Combination Antiretroviral Therapy. JAIDS Journal of Acquired Immune Deficiency Syndromes, 68(5), 568-577.
Gras L, de Wolf F, Smit C, Prins M, van der Meer JTM, Vanhommerig JW, Zwinderman AH, Schinkel J, Geskus RB (2015). Changes in HIV RNA and CD4 Cell Count After Acute HCV Infection in Chronically HIV-Infected Individuals. JAIDS Journal of Acquired Immune Deficiency Syndromes, 68(5), 536-542.
Lodi S, Phillips A, Logan R, Olson A, Costagliola D, Abgrall S, van Sighem A, Reiss P, Miró JM, Ferrer E, et al (2015). Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study. The Lancet HIV, 2(8), e335-e343.
Cohen S, Van Bilsen WPH, Smit C, Fraaij PLA, Warris A, Kuijpers TW, Geelen SPM, Wolfs TFW, Scherpbier HJ, Van Rossum AMC, et al (2015). Country of birth does not influence long-term clinical, virologic, and immunological outcome of HIV-infected children living in the Netherlands: a cohort study comparing children born in the Netherlands with children born in Sub-Saharan Africa. Journal of Acquired Immune Deficiency Syndromes, 68(2), 178-185.
Country of birth does not influence long-term clinical, virologic, and immunological outcome of HIV-infected children living in the Netherlands: a cohort study comparing children born in the Netherlands with children born in Sub-Saharan Africa
Immigrant HIV-infected adults in industrialized countries show a poorer clinical and virologic outcome compared with native patients. We aimed to investigate potential differences in clinical, immunological, and virologic outcome in Dutch HIV-infected children born in the Netherlands (NL) versus born in Sub-Saharan Africa (SSA) in a national cohort analysis. METHODS:: We included all HIV-infected children registered between 1996 and 2013. Descriptive statistics, mixed-effects models, and Cox proportional hazard models were used to investigate differences between groups. RESULTS:: in total, 319 HIV-infected children were registered. The majority of these children were born in SSA (n = 148, 47%) or NL (n = 113, 36%) and most were black (n = 158, 61%). Children born in NL were diagnosed at a median age of 1.2 years and initiated combination antiretroviral therapy (cART) at a median age of 2.6 years, compared with 3.7 and 5.3 years, respectively, for children born in SSA (HIV diagnosis: P < 0.001; cART initiation: P < 0.001). Despite a lower initial CD4 T-cell Z-score in children born in SSA, their immunological reconstitution was similar to children from NL. Virologic suppression was achieved in the majority of all cART-treated children (NL: 96%, SSA: 94%). There was no difference in the occurrence or timing of virologic failure. CONCLUSIONS:: Most immigrant HIV-infected children living in NL were born in SSA. Children born in SSA were diagnosed and initiated cART at an older age than children born in NL. Despite initial differences in CD4 T-cell counts and HIV viral load, the long-term immunological and virologic response to cART was similar in both groups.
Zoll J, Rahamat-Langendoen J, Ahout I, Jonge MID, Jans J, Huijnen MA, Ferwerda G, Warris A, Melchers WJG (2015). Direct multiplexed whole genome sequencing of respiratory tract samples reveals full viral genomic information. Journal of Clinical Virology, 66, 6-11.
Direct multiplexed whole genome sequencing of respiratory tract samples reveals full viral genomic information
Background: Acute respiratory tract infections (RTI) cause substantial morbidity during childhood, and are responsible for the majority of pediatric infectious diseases. Although most acute RTI are thought to be of viral origin, viral etiology is still unknown in a significant number of cases. Objectives: Multiplexed whole genome sequencing (WGS) was used for virome determination directly on clinical samples as proof of principle for the use of deep sequencing techniques in clinical diagnosis of viral infections. Study design: WGS was performed with nucleic acids from sputum and nasopharyngeal aspirates from four pediatric patients with known respiratory tract infections (two patients with human rhinovirus, one patient with human metapneumovirus and one patient with respiratory syncytial virus), and from four pediatric patients with PCR-negative RTI, and two control samples. Results: Viral infections detected by routine molecular diagnostic methods were confirmed by WGS; in addition, typing information of the different viruses was generated. In three out of four samples from pediatric patients with PCR-negative respiratory tract infections and the two control samples, no causative viral pathogens could be detected. In one sample from a patient with PCR-negative RTI, rhinovirus type-C was detected. Almost complete viral genomes could be assembled and in all cases virus species could be determined. Conclusions: Our study shows that, in a single run, viral pathogens can be detected and characterized, providing information for clinical assessment and epidemiological studies. We conclude that WGS is a powerful tool in clinical virology that delivers comprehensive information on the viral content of clinical samples.
Bhatt JM, Bush A, van Gerven M, Nissenkorn A, Renke M, Yarlett L, Taylor M, Tonia T, Warris A, Zielen S, et al (2015). ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia. Eur Respir Rev, 24(138), 565-581.
ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia.
Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial lung disease/pulmonary fibrosis. Malnutrition is a significant comorbidity. The increased radiosensitivity and increased risk of cancer should be borne in mind when requesting radiological investigations. Aggressive proactive monitoring and treatment of these various aspects of lung disease under multidisciplinary expertise in the experience of national multidisciplinary clinics internationally forms the basis of this statement on the management of lung disease in A-T. Neurological management is outwith the scope of this document.
Muilwijk EW, Lempers VJC, Burger DM, Warris A, Pickkers P, Aarnoutse RE, Brüggemann RJM (2015). Impact of special patient populations on the pharmacokinetics of echinocandins. Expert Review of Anti-Infective Therapy, 13(6), 799-815.
Impact of special patient populations on the pharmacokinetics of echinocandins
Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g. critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.
Verweij PE, Ananda-Rajah M, Andes D, Arendrup MC, Brüggemann RJ, Chowdhary A, Cornely OA, Denning DW, Groll AH, Izumikawa K, et al (2015). International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus. Drug Resistance Updates, 21-22, 30-40.
International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus
An international expert panel was convened to deliberate the management of azole-resistant aspergillosis. In culture-positive cases, in vitro susceptibility testing should always be performed if antifungal therapy is intended. Different patterns of resistance are seen, with multi-azole and pan-azole resistance more common than resistance to a single triazole. In confirmed invasive pulmonary aspergillosis due to an azole-resistant Aspergillus, the experts recommended a switch from voriconazole to liposomal amphotericin B (L-AmB; Ambisome®). In regions with environmental resistance rates of ≥10%, a voriconazole-echinocandin combination or L-AmB were favoured as initial therapy. All experts recommended L-AmB as core therapy for central nervous system aspergillosis suspected to be due to an azole-resistant Aspergillus, and considered the addition of a second agent with the majority favouring flucytosine. Intravenous therapy with either micafungin or L-AmB given as either intermittent or continuous therapy was recommended for chronic pulmonary aspergillosis due to a pan-azole-resistant Aspergillus. Local and national surveillance with identification of clinical and environmental resistance patterns, rapid diagnostics, better quality clinical outcome data, and a greater understanding of the factors driving or minimising environmental resistance are areas where research is urgently needed, as well as the development of new oral agents outside the azole drug class.
Brand HK, Ahout IML, De Ridder D, Van Diepen A, Li Y, Zaalberg M, Andeweg A, Roeleveld N, De Groot R, Warris A, et al (2015). Olfactomedin 4 serves as a marker for disease severity in pediatric respiratory syncytial virus (RSV) infection. PLoS ONE, 10(7).
Olfactomedin 4 serves as a marker for disease severity in pediatric respiratory syncytial virus (RSV) infection
Background: Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making. Methods: in a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort. Results: Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age. Conclusion: By combining genome-wide expression profiling of blood cell subsets with clinically wellannotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection.
Colbers A, Moltó J, Ivanovic J, Kabeya K, Hawkins D, Gingelmaier A, Taylor G, Weizsäcker K, Sadiq ST, Van der Ende M, et al (2015). Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women. Journal of Antimicrobial Chemotherapy, 70(2), 534-542.
Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women
Objectives: to describe the pharmacokinetics of darunavir in pregnant HIV-infected women in the third trimester and post-partum. Patients and methods: This was a non-randomized, open-label, multicentre, Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with darunavir (800/100 mg once daily or 600/100 mg twice daily) as part of their combination ART were included. Pharmacokinetic curves were recorded in the third trimester and post-partum. A cord blood sample and maternal sample were collected. The study is registered at ClinicalTrials.gov under number NCT00825929. Results: Twenty-four women were included in the analysis [darunavir/ritonavir: 600/100 mg twice daily (n=6); 800/100 mg once daily (n=17); and 600/100 mg once daily (n=1)]. Geometric mean ratios of third trimester versus post-partum (90% CI) were 0.78 (0.60-1.00) for total darunavir AUC0-tau after 600/100 mg twice-daily dosing and 0.67 (0.56-0.82) for total darunavir AUC0-tau after 800/100 mg once-daily dosing. The unbound fraction of darunavir was not different during pregnancy (12%) compared with post-partum (10%). The median (range) ratio of darunavir cord blood/maternal blood was 0.13 (0.08-0.35). Viral load close to delivery was
van der Linden JWM, Arendrup MC, Warris A, Lagrou K, Pelloux H, Hauser PM, Chryssanthou E, Mellado E, Kidd SE, Tortorano AM, et al (2015). Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus. Emerging Infectious Diseases, 21(6), 1041-1044.
Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus
To investigate azole resistance in clinical Aspergillus isolates, we conducted prospective multicenter international surveillance. A total of 3,788 Aspergillus isolates were screened in 22 centers from 19 countries. Azole-resistant A. fumigatus was more frequently found (3.2% prevalence) than previously acknowledged, causing resistant invasive and noninvasive aspergillosis and severely compromising clinical use of azoles.
Zhang S, van Sighem A, Kesselring A, Gras L, Prins JM, Hassink E, Kauffmann R, Richter C, de Wolf F, Reiss P, et al (2015). Risk of non-AIDS-defining events among HIV-infected patients not yet on antiretroviral therapy. HIV Medicine, 16(5), 265-272.
Achhra AC, Mocroft A, Reiss P, Sabin C, Ryom L, de Wit S, Smith CJ, d'Arminio Monforte A, Phillips A, Weber R, et al (2015). Short-term weight gain after antiretroviral therapy initiation and subsequent risk of cardiovascular disease and diabetes: the D:A:D study. HIV Medicine, 17(4), 255-268.
Lestner JM, Versporten A, Doerholt K, Warris A, Roilides E, Sharland M, Bielicki J, Goossens H (2015). Systemic antifungal prescribing in neonates and children: Outcomes from the antibiotic resistance and prescribing in european children (arpec) study. Antimicrobial Agents and Chemotherapy, 59(2), 782-789.
Systemic antifungal prescribing in neonates and children: Outcomes from the antibiotic resistance and prescribing in european children (arpec) study
The appropriate use of systemic antifungals is vital in the prevention and treatment of invasive fungal infection (IFI) in immunosuppressed children and neonates. This multicenter observational study describes the inpatient prescribing practice of antifungal drugs for children and neonates and identifies factors associated with prescribing variability. A single-day point prevalence study of antimicrobial use in hospitalized neonates and children was performed between October and December 2012. The data were entered through a study-specific Web-based portal using a standardized data entry protocol. Data were recorded from 17,693 patients from 226 centers. A total of 136 centers recorded data from 1,092 children and 380 neonates receiving at least one antifungal agent. The most frequently prescribed systemic antifungals were fluconazole (n = 355) and amphotericin B deoxycholate (n =195). The most common indications for antifungal administration in children were medical prophylaxis (n = 325), empirical treatment of febrile neutropenia ( n = 122), and treatment of confirmed or suspected IFI (n = 100 [14%]). The treatment of suspected IFI in low-birthweight neonates accounted for the majority of prescriptions in the neonatal units (n = 103). An analysis of variance (ANOVA) demonstrated no significant effect of clinical indication (prophylaxis or treatment of systemic or localized infection) on the total daily dose (TDD). Fewer than one-half of the patients (n - 371) received a TDD within the dosing range recommended in the current guidelines. Subtherapeutic doses were prescribed in 416 cases (47%). The predominance of fluconazole and high incidence of subtherapeutic doses in participating hospitals may contribute to suboptimal clinical outcomes and an increased predominance of resistant pathogenic fungi. A global consensus on antifungal dosing and coordinated stewardship programs are needed to promote the consistent and appropriate use of antifungal drugs in neonates and children.
Schatorjé EJH, Van Der Steeg H, Stelma F, Hebeda K, Warris A (2014). Borrelial lymphocytoma. Nederlands Tijdschrift voor Geneeskunde, 158(17).
Borrelial lymphocytoma
Background: Skin is the most frequently affected tissue in Lyme disease with an erythema migrans as the most important and known clinical entity. Other dermatologic manifestations are less known and therefore can lead to diagnostic delay. We present a case of a less frequent but also typical presentation of Lyme disease: Borrelial lymphocytoma. Case: a 16-year old boy presented with a swollen, red and painful nipple since several months. An ultrasound showed normal breast tissue. The patient was referred to the pediatric surgeon who performed an incision biopsy. Pathological examination revealed follicular hyperplasia without signs of malignancy and an infectious cause, most likely Lyme disease, was suspected. The boy did not recall a tick bite, neither an erythema migrans. However, serological analysis and PCR of the tissue confirmed the diagnosis of a Borrelial lymphocytoma. The patient was treated with doxycycline with good result. Conclusion: Lyme disease, caused by bacteria of the spirochaete family grouped in the Borrelia burgdorferi sensu lato, has several clinical manifestations. Borrelial lymphocytoma is considered a sub-acute skin manifestation of an early disseminated infection. It is a relatively rare but also typical presentation of Lyme disease with local cutaneous benign B-cell lymphoproliferation at the site of the bacterial infection. Predilection sites are the ears in children and chest/nipples in adults. Treatment is like an erythema migrans with doxycycline in older children (>8 years) and adults, or amoxicillin in young children leading to a good prognosis. Early recognition of this characteristic clinical presentation prevents unnecessary diagnostic test and diagnosis can be made by physical examination confirmed by serological tests.
Gathmann B, Mahlaoui N, Gérard L, Oksenhendler E, Warnatz K, Schulze I, Kindle G, Kuijpers TW, van Beem RT, Guzman D, et al (2014). Clinical picture and treatment of 2212 patients with common variable immunodeficiency. Journal of Allergy and Clinical Immunology, 134(1), 116-126.e11.
Westra D, Kurvers RAJ, Van den Heuvel LP, Würzner R, Hoppenreijs EPAH, Van der Flier M, Van de Kar NCAJ, Warris A (2014). Compound heterozygous mutations in the C6 gene of a child with recurrent infections. Molecular Immunology, 58(2), 201-205.
Compound heterozygous mutations in the C6 gene of a child with recurrent infections
The complement system plays an important role in both the innate and adaptive immune system. Patients with inherited complement deficiencies have an increased risk of systemic bacterial infections. Deficiencies of the terminal complement pathway are especially associated with invasive meningococcal disease.Here, we report a case of a boy that presented with arthritis and recurrent bacterial and viral infections. Extensive analyses revealed decreased complement activity of both classical and alternative pathway, indicating a deficiency of C3 or one of the factors of the terminal complement pathway.Mutational analysis of the C6 gene identified two compound heterozygous mutations. An unknown missense aberration was found that involves the loss of a cysteine, possibly affecting the 3D structure of the protein. Furthermore, a known splice site variation was identified that results in a 14% shorter protein, due to transcription of amino acids that are normally intronic until a stop codon is reached (exon-intron boundary defect). It is known that the protein with this latter aberration is still functionally active when present with other C6 mutations and therefore, the consequences of the combination of the identified variations have been studied. Quantitative ELISAs showed that at least one allele produced a circulating C6 molecule that can be incorporated in the membrane attack complex, likely the truncated protein.In the present case we observed relapsing bacterial and viral infections, but no meningococcal disease. The reduced complement activity can be explained by the identified genetic variations in C6, as recombinant C6 supplementation corrected complement function in vitro. © 2013 Elsevier Ltd.
Kamara DA, Ryom L, Ross M, Kirk O, Reiss P, Morlat P, Moranne O, Fux CA, Mocroft A, Sabin C, et al (2014). Development of a definition for Rapid Progression (RP) of renal function in HIV-positive persons: the D:A:D study. BMC Nephrology, 15(1).
Murray JE, Bicknell LS, Yigit G, Duker AL, van Kogelenberg M, Haghayegh S, Wieczorek D, Kayserili H, Albert MH, Wise CA, et al (2014). Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency. Human Mutation, 35(1), 76-85.
Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency
Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d. height -5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype-phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder. © 2013 the Authors. Human Mutation published by Wiley Periodicals, Inc.
Groll AH, Castagnola E, Cesaro S, Dalle JH, Engelhard D, Hope W, Roilides E, Styczynski J, Warris A, Lehrnbecher T, et al (2014). Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. The Lancet Oncology, 15(8).
Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation
Invasive opportunistic fungal diseases (IFDs) are important causes of morbidity and mortality in paediatric patients with cancer and those who have had an allogeneic haemopoietic stem-cell transplantation (HSCT). Apart from differences in underlying disorders and comorbidities relative to those of adults, IFDs in infants, children, and adolescents are unique with respect to their epidemiology, the usefulness of diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of interventional phase 3 clinical trials for guidance of evidence-based decisions. To better define the state of knowledge on IFDs in paediatric patients with cancer and allogeneic HSCT and to improve IFD diagnosis, prevention, and management, the Fourth European Conference on Infections in Leukaemia (ECIL-4) in 2011 convened a group that reviewed the scientific literature on IFDs and graded the available quality of evidence according to the Infectious Diseases Society of America grading system. The final considerations and recommendations of the group are summarised in this manuscript. © 2014 Elsevier Ltd.
Rokx C, Fibriani A, van de Vijver DAMC, Verbon A, Schutten M, Gras L, Rijnders BJA, Prins JM, Kuijpers TW, Scherpbier HJ, et al (2014). Increased Virological Failure in Naive HIV-1-Infected Patients Taking Lamivudine Compared with Emtricitabine in Combination with Tenofovir and Efavirenz or Nevirapine in the Dutch Nationwide ATHENA Cohort. Clinical Infectious Diseases, 60(1), 143-153.
Petoumenos K, Reiss P, Ryom L, Rickenbach M, Sabin CA, El-Sadr W, d'Arminio Monforte A, Phillips AN, De Wit S, Kirk O, et al (2014). Increased risk of cardiovascular disease (CVD) with age in HIV-positive men: a comparison of the D:A:D CVD risk equation and general population CVD risk equations. HIV Medicine, n/a-n/a.
Warris A, Henriet SSV (2014). Invasive fungal infections in the child with chronic granulomatous disease. Current Fungal Infection Reports, 8(1), 37-44.
Invasive fungal infections in the child with chronic granulomatous disease
Invasive fungal infections (IFI) are a major threat for patients with chronic granulomatous disease (CGD) which is an inherited disorder of NADPH oxidase. The absence of a functional NADPH oxidase complex affects the display of an efficient antimicrobial effect as well as a controlled inflammatory response. Invasive aspergillosis caused by either Aspergillus fumigatus or A. nidulans is the most common IFI. Aspergillus nidulans infections seem to display a unique interaction with the CGD host and are seldom reported in other immunocompromised hosts. The occurrence of mucormycosis in the CGD host is mainly noted in the setting of treatment of inflammatory complications with immunosuppressive drugs. Candida infections are infrequently seen and show an age-dependent clinical presentation mainly affecting infants and young children. Furthermore, the child with CGD is susceptible to a wide range of fungal pathogens, indicating the need to determine the causative fungus, often by invasive diagnostic approaches, to guide optimal and rational treatment. Currently, it is becoming more and more clear that the exaggerated inflammatory response to fungal infection in the CGD host is leading in the pathogenesis, and antiinflammatory treatment might become as important as antifungal treatment in this specific host. © 2014 Springer Science+Business Media.
de Boer M, van Leeuwen K, Geissler J, Weemaes CM, van den Berg TK, Kuijpers TW, Warris A, Roos D (2014). Primary Immunodeficiency Caused by an Exonized Retroposed Gene Copy Inserted in the CYBB Gene. Human Mutation, 35(4), 486-496.
Primary Immunodeficiency Caused by an Exonized Retroposed Gene Copy Inserted in the CYBB Gene
Retrotransposon-mediated insertion of a long interspersed nuclear element (LINE)-1 or an Alu element into a human gene is a well-known pathogenic mechanism. We report a novel LINE-1-mediated insertion of a transcript from the TMF1 gene on chromosome 3 into the CYBB gene on the X-chromosome. In a Dutch male patient with chronic granulomatous disease, a 5.8-kb, incomplete and partly exonized TMF1 transcript was identified in intron 1 of CYBB, in opposite orientation to the host gene. The sequence of the insertion showed the hallmarks of a retrotransposition event, with an antisense poly(A) tail, target site duplication, and a consensus LINE-1 endonuclease cleavage site. This insertion induced aberrant CYBB mRNA splicing, with inclusion of an extra 117-bp exon between exons 1 and 2 of CYBB. This extra exon contained a premature stop codon. The retrotransposition took place in an early stage of fetal development in the mother of the patient, because she showed a somatic mosaicism for the mutation that was not present in the DNA of her parents. However, the mutated allele was not expressed in the patient's mother because the insertion was found only in the methylated fraction of her DNA. © 2014 WILEY PERIODICALS, INC.
Broenen E, Mavinkurve-Groothuis A, Kamphuis-Van Ulzen K, Brüggemann R, Verweij P, Warris A (2014). Screening of the central nervous system in children with invasive pulmonary aspergillosis. Medical Mycology Case Reports, 4(1), 8-11.
Screening of the central nervous system in children with invasive pulmonary aspergillosis
The existing guidelines regarding the management of invasive pulmonary aspergillosis do not recommend screening of the extra-pulmonary sites. Due to the fact that the presence of central nervous system (CNS) aspergillosis will influence treatment decisions regarding which antifungal to use and the aimed target concentrations of azoles in plasma, to be informed about dissemination of the infection to the CNS is absolutely necessary. We demonstrate the need for a structured approach to screening of pediatric patients for CNS aspergillosis. © 2014 the Authors.
Kurvers RAJ, Westra D, van Heijst AF, Walk TLM, Warris A, van de Kar NCAJ (2014). Severe infantile Bordetella pertussis pneumonia in monozygotic twins with a congenital C3 deficiency. European Journal of Pediatrics, 173(12), 1591-1594.
Severe infantile Bordetella pertussis pneumonia in monozygotic twins with a congenital C3 deficiency
Abstract: Bordetella pertussis or whooping cough is a vaccine-preventable disease that still remains a serious infection in neonates and young infants. We describe two young infants, monozygotic twins, with a severe B. pertussis pneumonia of whom one needed extracorporeal membrane oxygenation. Diagnostic work-up of unexplained hematuria and proteinuria during the illness revealed low serum complement component 3 (C3) levels. During follow-up, C3 levels remained low (400–600 mg/L). Extensive analysis of the persistent low C3 levels revealed an unknown heterozygous mutation in the C3 gene in both siblings and their mother. This C3 mutation in combination with the specific virulence mechanisms of B. pertussis probably contributed to the severe disease course in these cases. Conclusion: We propose that genetically caused complement disorders should be considered when confronted with severe cases of B. pertussis infection.
Schatorjé EJH, Gathmann B, Van Hout RWNM, De Vries E, Alsina L, Baumann U, Belohradsky BH, Bienemann K, Boardman B, Borte M, et al (2014). The PedPAD study: Boys predominate in the hypogammaglobulinaemia registry of the ESID online database. Clinical and Experimental Immunology, 176(3), 387-393.
The PedPAD study: Boys predominate in the hypogammaglobulinaemia registry of the ESID online database
Hypogammaglobulinaemias are the most common primary immunodeficiency diseases. This group of diseases is very heterogeneous, and little is known about these diseases in children. In the Pediatric Predominantly Antibody Deficiencies (PedPAD) study, we analysed data from the European Society for Immunodeficiencies (ESID) online database to gain more insight into the characteristics of children with hypogammaglobulinaemia; 46 centres in 18 different countries agreed to participate. Data from 2076 of the 3191 children who were registered at the time of data extraction with a diagnosis of hypogammaglobulinaemia (this excludes agammaglobulinaemia and defects in class-switch recombination) were available for analysis. The data set showed several limitations. Because of country-related differences in diagnostic criteria used for the classification of different types of primary hypogammaglobulinaemia, further analysis of the data was performed in the combined data set. The most striking observation is the strong majority of male patients in the group of children with primary hypogammaglobulinaemia (n=1292, 63%). This male predominance was observed in each of the 18 countries involved. The boys were younger at diagnosis (mean age males 5·3 years; mean age females 5·8 years). Moreover, one or more complications were more frequently reported in boys (12%) compared to girls (5%). The male predominance suggests that patients with an undetected or unknown X-linked genetic cause are included in this group of children registered as primary hypogammaglobulinaemia. © 2014 British Society for Immunology.
Warris A (2014). The biology of pulmonary aspergillus infections. Journal of Infection, 69(S1), S36-S41.
The biology of pulmonary aspergillus infections
Pulmonary aspergillus infections are mainly caused by Aspergillus fumigatus and can be classified based on clinical syndromes into saphrophytic infections, allergic disease and invasive disease. Invasive pulmonary aspergillosis, occurring in immunocompromised patients, reflects the most serious disease with a high case-fatality rate. Patients with cystic fibrosis and severe asthma might develop allergic bronchopulmonary aspergillosis, while saphrophytic infections are observed in patients with lung cavities mainly due to tuberculosis. Histopathologically, a differentiation can be made into angio-invasive and airway-invasive disease. If the host response is too weak or too strong, Aspergillus species are able to cause disease characterized either by damage from the fungus itself or through an exaggerated inflammatory response of the host, in both situations leading to overt disease associated with specific clinical signs and symptoms. The unraveling of the specific host - Aspergillus interaction has not been performed to a great extent and needs attention to improve the management of those clinical syndromes.
Driessen GJ, Ijspeert H, Weemaes CMR, Haraldsson A, Trip M, Warris A, Van Der Flier M, Wulffraat N, Verhagen MMM, Taylor MA, et al (2013). Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. Journal of Allergy and Clinical Immunology, 131(5).
Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity
Background: Ataxia telangiectasia (AT) is a multisystem DNA-repair disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. Patients with AT have reduced B- and T-cell numbers and a highly variable immunodeficiency. ATM is important for V(D)J recombination and immunoglobulin class-switch recombination (CSR); however, little is known about the mechanisms resulting in antibody deficiency severity. Objective: We sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT. Methods: in this study we included patients with classical AT plus early-onset hypogammaglobulinemia (n = 3), classical AT (n = 8), and variant AT (late onset, n = 4). We studied peripheral B- and T-cell subsets, B-cell subset replication history, somatic hypermutation frequencies, CSR patterns, B-cell repertoire, and ATM kinase activity. Results: Patients with classical AT lacked ATM kinase activity, whereas patients with variant AT showed residual function. Most patients had disturbed naive B-cell and T-cell homeostasis, as evidenced by low cell numbers, increased proliferation, a large proportion CD21lowCD38low anergic B cells, and decreased antigen receptor repertoire diversity. Impaired formation of T cell-dependent memory B cells was predominantly found in patients with AT plus hypogammaglobulinemia. These patients had extremely low naive CD4+ T-cell counts, which were more severely reduced compared with those seen in patients with classical AT without hypogammaglobulinemia. Finally, AT deficiency resulted in defective CSR to distal constant regions that might reflect an impaired ability of B cells to undergo multiple germinal center reactions. Conclusion: the severity of the antibody deficiency in patients with AT correlates with disturbances in B- and T-cell homeostasis resulting in reduced immune repertoire diversity, which consequently affects the chance of successful antigen-dependent cognate B-T interaction. © 2012 American Academy of Allergy, Asthma & Immunology.
Verhagen LM, Luesink M, Warris A, De Groot R, Hermans PWM (2013). Bacterial respiratory pathogens in children with inherited immune and airway disorders: Nasopharyngeal carriage and disease risk. Pediatric Infectious Disease Journal, 32(4), 399-404.
Bacterial respiratory pathogens in children with inherited immune and airway disorders: Nasopharyngeal carriage and disease risk
Children with primary immunodeficiencies, sickle cell disease and cystic fibrosis are at risk to develop invasive bacterial infections caused by respiratory tract pathogens, in particular Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. This review article evaluates the role of nasopharyngeal colonization by these pathogens in the high prevalence of respiratory and invasive infections in children with inherited disorders affecting the immune system or the respiratory tract. We conclude that respiratory and invasive diseases that occur in children with primary immunodeficiencies or sickle cell disease are probably a result of increased nasopharyngeal colonization rates compared with healthy children. However, when the inherited disorder is characterized by local airway abnormalities such as in cystic fibrosis, enhanced nasopharyngeal colonization does not seem to play a major role in invasive disease risk. As the evidence for the role of nasopharyngeal colonization in disease risk in these specific patient groups partly comes from experimental studies and animal models, longitudinal studies in children are needed. Detailed understanding of the effect of colonization on the development of respiratory and invasive infections in children with primary immunodeficiencies, sickle cell disease or cystic fibrosis provides a justification for the selective introduction of vaccination and prophylactic antibiotic treatment. Recommendations for the use of (preventive) therapeutic strategies in these patient groups taking into account disease-specific immunologic mechanisms underlying colonization and disease are described. Copyright © 2013 by Lippincott Williams & Wilkins.
Schoenaker MHD, Otten B, Finken MJJ, Michiels E, Van Noesel MM, Loeffen J, Warris A, Noordam C, Weemaes CM (2013). Bloom syndrome: Timely diagnosis before growth hormone therapy is being considered. Tijdschrift voor Kindergeneeskunde, 81(6), 142-148.
Bloom syndrome: Timely diagnosis before growth hormone therapy is being considered
Bloom syndrome (BS) is a rare DNA-repair disorder. The disease can be recognized at an early age by the most characteristic symptoms: pre- and postnatal growth retardation and a butterflyshaped facial erythema in the face. We discuss the symptoms leading to the diagnosis in seven patients with BS. Patients with BS have a high risk to develop a malignancy. Treatment with growth hormone in Bloom patients could possibly increase the risk on developing a malignancy. To consider growth hormone therapy in Bloom patients, the diagnosis BS should be made in time. © 2013 Bohn, Stafleu van Loghum.
Schatorjé EJH, van der Steeg H, Stelma F, Hebeda K, Warris A (2013). Borrelia-lymfocytoom. Nederlands tijdschrift voor geneeskunde, 157
Borrelia-lymfocytoom
Borrelial lymphocytoma is a relatively rare but typical presentation of Lyme disease. Predilection sites are the ears in children and chest/nipples in adults. It is treated like an erythema migrans and has a good prognosis. A 16-year-old boy presented with a swollen, red and painful right nipple since several months. An ultrasound showed normal breast tissue. The patient was referred to the pediatric surgeon who performed an incision biopsy. Histopathological examination revealed follicular hyperplasia without signs of malignancy. An infectious cause, most likely Lyme disease, was suspected. Serological analysis and PCR of the tissue confirmed the diagnosis of a borrelial lymphocytoma, and the patient was treated with doxycycline with good result. Early recognition of the characteristic clinical presentation of borrelial lymphocytoma, supported by positive results from serologic testing for Lyme disease, avoids the need for additional and invasive diagnostic tests.
Brand HK, Ferwerda G, Preijers F, de Groot R, Neeleman C, Staal FJT, Warris A, Hermans PWM (2013). CD4+ T-cell counts and interleukin-8 and CCL-5 plasma concentrations discriminate disease severity in children with RSV infection. Pediatr Res, 73(2), 187-193.
CD4+ T-cell counts and interleukin-8 and CCL-5 plasma concentrations discriminate disease severity in children with RSV infection.
BACKGROUND: Current tools to predict the severity of respiratory syncytial virus (RSV) infection might be improved by including immunological parameters. We hypothesized that a combination of inflammatory markers would differentiate between severe and mild disease in RSV-infected children. METHODS: Blood and nasopharyngeal samples from 52 RSV-infected children were collected during acute infection and after recovery. Retrospectively, patients were categorized into three groups based on disease severity: mild (no supportive treatment), moderate (supplemental oxygen and/or nasogastric feeding), and severe (mechanical ventilation). Clinical data, number of flow-defined leukocyte subsets, and cytokine concentrations were compared. RESULTS: Children with severe RSV infection were characterized by young age; lymphocytopenia; increased interleukin (IL)-8, granulocyte colony-stimulating factor (G-CSF), and IL-6 concentrations; and decreased chemokine (C-C motif) ligand (CCL-5) concentrations in plasma. The combination of plasma levels of IL-8 and CCL-5, and CD4+ T-cell counts, with cutoff values of 67 pg/ml, 13 ng/ml, and 2.3 × 10(6)/ml, respectively, discriminated severe from mild RSV infection with 82% sensitivity and 96% specificity. CONCLUSION: This study demonstrates that the combination of CD4+ T-cell counts and IL-8 and CCL-5 plasma concentrations correlates with disease severity in RSV-infected children. In addition to clinical features, these immunological markers may be used to assess severity of RSV infection and guide clinical management.
Smit M, Smit C, Geerlings S, Gras L, Brinkman K, Hallett TB, de Wolf F (2013). Changes in First-Line cART Regimens and Short-Term Clinical Outcome between 1996 and 2010 in the Netherlands. PLoS ONE, 8(9), e76071-e76071.
Henriet SSV, Jans J, Simonetti E, Kwon-Chung KJ, Rijs AJMM, Hermans PWM, Holland SM, De Jonge MI, Warris A (2013). Chloroquine modulates the fungal immune response in phagocytic cells from patients with chronic granulomatous disease. Journal of Infectious Diseases, 207(12), 1932-1939.
Chloroquine modulates the fungal immune response in phagocytic cells from patients with chronic granulomatous disease
Invasive aspergillosis is a major threat to patients with chronic granulomatous disease (CGD). Fungal pathogenesis is the result of a diminished antifungal capacity and dysregulated inflammation. A deficient NADPH-oxidase complex results in defective phagolysosomal alkalization. To investigate the contribution of defective pH regulation in phagocytes among patients with CGD during fungal pathogenesis, we evaluated the effect of the acidotropic, antimalarial drug chloroquine (CQ) on the antifungal capacity of polymorphonuclear cells (PMNs) and on the inflammatory response of peripheral blood mononuclear cells (PBMCs). Chloroquine exerted a direct pH-dependent antifungal effect on Aspergillus fumigatus and Aspergillus nidulans; it increased the antifungal activity of PMNs from patients with CGD at a significantly lower concentration, compared with the concentration for PMNs from healthy individuals; and decreased the hyperinflammatory state of PBMCs from patients with CGD, as observed by decreased tumor necrosis factor α and interleukin 1β release. Chloroquine targets both limbs of fungal pathogenesis and might be of great value in the clearance of invasive aspergillosis in patients with CGD. © 2013 the Author. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.
Ijspeert H, Warris A, van der Flier M, Reisli I, Keles S, Chishimba S, van Dongen JJM, van Gent DC, Van der Burg M (2013). Clinical Spectrum of LIG4 Deficiency is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities. Human Mutation, 34(12), 1611-1614.
Clinical Spectrum of LIG4 Deficiency is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities
DNA double-strand break repair via non-homologous end joining (NHEJ) is involved in recombination of immunoglobulin and T-cell receptor genes. Mutations in NHEJ components result in syndromes that are characterized by microcephaly and immunodeficiency. We present a patient with lymphopenia, extreme radiosensitivity, severe dysmaturity, corpus callosum agenesis, polysyndactily, dysmorphic appearance, and erythema, which are suggestive of a new type of NHEJ deficiency. We identified two heterozygous mutations in LIG4. The p.S205LfsX29 mutation results in lack of the nuclear localization signal and appears to be a null mutation. The second mutation p.K635RfsX10 lacks the C-terminal region responsible for XRCC4 binding and LIG4 stability and activity, and therefore this mutant might be a null mutation as well or have very low residual activity. This is remarkable since Lig4 knockout mice are embryonic lethal and so far in humans no complete LIG4 deficiencies have been described. This case broadens the clinical spectrum of LIG4 deficiencies. © 2013 the Authors. Human Mutation published by Wiley Periodicals, Inc.
Driessen GJ, Dalm VASH, van Hagen PM, Anne Grashoff H, Hartwig NG, van Rossum AMC, Warris A, de Vries E, Barendregt BH, Pico I, et al (2013). Common variable immunodeficiency and idiopathic primary hypogammaglobulinemia: Two different conditions within the same disease spectrum. Haematologica, 98(10), 1617-1623.
Common variable immunodeficiency and idiopathic primary hypogammaglobulinemia: Two different conditions within the same disease spectrum
Patients with hypogammaglobulinemia who do not fulfill all the classical diagnostic criteria for common variable immunodeficiency (reduction of two immunoglobulin isotypes and a reduced response to vaccination) constitute a diagnostic and therapeutic dilemma, because information concerning the clinical and immunological characteristics of these patients with idiopathic primary hypogammaglobulinemia is not available. In 44 common variable immunodeficiency and 21 idiopathic primary hypogammaglobulinemia patients we determined the clinical phenotypes and performed flow cytometric immunophenotyping to assess the pathophysiological B-cell patterns and memory B-cell subset counts. Age-matched B-cell subset reference values of 130 healthy donors were generated. Severe pneumonia and bronchiectasis occurred at similar frequencies in idiopathic primary hypogammaglobulinemia and common variable immunodeficiency. Although IgG levels were only moderately reduced compared to common variable immunodeficiency, 12 of 21 idiopathic primary hypogammaglobulinemia patients required immunoglobulin replacement. Non-infectious disease-related clinical phenotypes (autoimmune cytopenia, polyclonal lymphocytic proliferation and persistent unexplained enteropathy) were exclusively observed in common variable immunodeficiency and were associated with early peripheral B-cell maturation defects or B-cell survival defects. T-cell dependent memory B-cell formation was more severely affected in common variable immunodeficiency. Furthermore, 14 of 21 idiopathic primary hypogammaglobulinemia patients showed normal peripheral Bcell subset counts, suggestive for a plasma cell defect. In conclusion, idiopathic primary hypogammaglobulinemia patients who do not fulfill all diagnostic criteria of common variable immunodeficiency have moderately decreased immunoglobulin levels and often a normal peripheral B-cell subset distribution, but still suffer from serious infectious complications. © 2013 Ferrata Storti Foundation.
De Mol M, De Jongste JC, Van Westreenen M, Merkus PJFM, De Vries AHC, Hop WCJ, Warris A, Janssens HM (2013). Diagnosis of invasive pulmonary aspergillosis in children with bronchoalveolar lavage galactomannan. Pediatric Pulmonology, 48(8), 789-796.
Diagnosis of invasive pulmonary aspergillosis in children with bronchoalveolar lavage galactomannan
Background Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in immunocompromised patients. Early diagnosis and therapy improves outcome. Assessment of galactomannan (GM) in bronchoalveolar lavage (BAL) fluid is a proposed tool to diagnose IPA. Little is known about the diagnostic value of BAL GM in children. Materials and Methods Retrospectively, 72 bronchoscopies were analyzed for GM in patients fulfilling the host factor criteria as defined by the EORTC/MSG. A cut-off index value GM of ≥0.5 was used. Clinical data, results of chest CT-scans and BAL cultures were collected. Results Sensitivity, specificity, PPV, and NPV of BAL GM for a diagnosis of proven and probable IPA (n = 41) were 82.4%, 87.5%, 82.4%, and 87.5% respectively. A significant relation was found for BAL GM and abnormal chest CT (P = 0.01). No significant relationship was observed between BAL Aspergillus sp. culture and chest CT (n = 47). BAL GM and serum GM correlated significantly. In 9 out of 12 patients classified as possible IPA, antifungal therapy was continued or started, despite a negative BAL GM. Conclusions BAL GM test had good diagnostic value in children suspected of IPA. However, the decision to continue or start antifungal therapy was mainly determined by the clinical suspicion of IPA based on chest CT-outcome, serum GM index values and failure of antibiotic therapy. © 2012 Wiley Periodicals, Inc.
Kinabo GD, van der Ven A, Msuya LJ, Shayo AM, Schimana W, Ndaro A, van Asten HAGH, Dolmans WMV, Warris A, Hermans PWM, et al (2013). Dynamics of nasopharyngeal bacterial colonisation in HIV-exposed young infants in Tanzania. Tropical Medicine and International Health, 18(3), 286-295.
Dynamics of nasopharyngeal bacterial colonisation in HIV-exposed young infants in Tanzania
Objectives: to estimate the prevalence of nasopharyngeal bacterial colonisation (NPBC) patterns in young Tanzanian HIV-exposed infants and to analyse the influence of maternal NPBC and of the infant's HIV status on the NPBC pattern. Methods: Longitudinal cohort study of neonates born to HIV-infected mothers visiting Kilimanjaro Christian Medical Centre, Tanzania, between 2005 and 2009. Demographic and clinical data and nasopharyngeal bacterial cultures were obtained at the age of 6 weeks, 3 and 6 months, and at one time point, a paired mother-infant nasopharyngeal swab was taken. Results: Four hundred and twenty-two swabs were taken from 338 eligible infants. At 6 weeks of age, colonisation rates were 66% for Staphylococcus aureus, 56% for Streptococcus pneumoniae, 50% for Moraxella catarrhalis and 14% for Haemophilus influenzae. Colonisation with S. aureus diminished over time and was more common in HIV-infected infants. S. pneumoniae and H. influenzae colonisation rose over time and was more prevalent in HIV-uninfected children. Co-colonisation of S. pneumoniae with H. influenzae or M. catarrhalis was mostly noticed in HIV-infected infants. S. pneumoniae and M.catarrhalis colonisation of the mother was a risk factor for colonisation in HIV-uninfected infants, while maternal S. aureus colonisation was a risk factor for colonisation in HIV-infected infants. Among the 104 S. pneumoniae isolates, 19F was most prevalent, and 57 (55%) displayed capsular serotypes represented in the 13-valent pneumococcal conjugate vaccine. Conclusions: NPBC was common in Tanzanian HIV-exposed infants. The significant prevalence of pneumococcal vaccine serotypes colonising this paediatric population justifies the use of the 13-valent pneumococcal vaccine to reduce the burden of pneumococcal invasive disease. © 2013 Blackwell Publishing Ltd.
Opstelten W, Ruijs WL, Warris A, van Binnendijk RS, Wolfs TFW, Hahné SJM (2013). Er heerst weer mazelen. Nederlands tijdschrift voor geneeskunde, 157
Er heerst weer mazelen
Since the vaccination of Dutch children against the measles through the National Immunisation Programme started in 1976, the incidence of measles has greatly decreased. Local epidemics do still occur, however; these are largely confined to minority groups of orthodox Protestants who object to vaccination on religious grounds. A local epidemic of the measles has been developing in the Netherlands since May of this year, predominantly within unvaccinated groups where the highly contagious virus can easily spread. We describe an unvaccinated 10-year-old boy with an uncomplicated case of the measles and an unvaccinated 9-year-old boy who developed encephalitis as a complication of the measles. From the waning of maternal antibodies until the first regular vaccination and where herd immunity is lacking, children are at risk of the measles. For this reason, an extra (age
Jans J, Brüggemann RJM, Christdmann V, Verweij PE, Warris A (2013). Favorable outcome of neonatal cerebrospinal fluid shunt-associated Candida meningitis with caspofungin. Antimicrobial Agents and Chemotherapy, 57(5), 2391-2393.
Favorable outcome of neonatal cerebrospinal fluid shunt-associated Candida meningitis with caspofungin
Invasive Candida infections associated with medical devices are very difficult to cure without device removal. We present a case of neonatal cerebrospinal fluid shunt-associated Candida meningitis, in which removal of the device was precluded, that was successfully treated with caspofungin. Pharmacokinetic assessment of caspofungin concentrations in cerebrospinal fluid showed that exposure was adequate in the presence of a high systemic exposure. In complex cases of neonatal Candida infections involving medical devices, the addition of caspofungin might be beneficial. Copyright © 2013, American Society for Microbiology. All Rights Reserved.
Van Helmond LPFM, Maartens IA, Van Pelt-Koops JC, Henriet S, Hopman J, Pelleboer RAA, Warris A (2013). Fever without borders. Tijdschrift voor Kindergeneeskunde, 81(5), 135-137.
Fever without borders
Visceral leishmaniasis is endemic in tropical and subtropical areas worldwide, particularly Central and South America, the Middle-East, India, southern Europe, North and East Africa. In Europe, visceral leishmaniasis has been reported from Greece, Spain, the Balearic Islands, up to Northern Italy and Germany. Due to holidays to and increasing migration from these areas, this tropical disease is increasingly recognized in non-endemic countries. This case report describes a two-year-old Dutch boy suffering from visceral leishmaniasis, who had never entered an endemic area in his life. Despite extensive research, the source of transmission remained unclear. Therefore, in a child with fever, a pancytopenia and (hepato) splenomegaly, visceral leishmaniasis should not be excluded solely on the basis of a negative travelling history. Additional laboratory studies are required to exclude this potential lethal disease. © 2013 Bohn, Stafleu van Loghum. Literatuur:.
Henriet S, Verweij PE, Holland SM, Warris A (2013). Invasive fungal infections in patients with chronic granulomatous disease. Advances in Experimental Medicine and Biology, 764, 27-55.
Invasive fungal infections in patients with chronic granulomatous disease
Invasive fungal infections are a major threat for chronic granulomatous disease (CGD) patients. The present study provides a comprehensive overview of published invasive fungal infections in the CGD host through an extensive review of epidemiological, clinical, diagnostic and therapeutic data. In addition to the often mild clinical presentation, the currently used diagnostics for invasive aspergillosis have low sensitivity in CGD patients and cannot be easily translated to this non-neutropenic host. Aspergillus fumigatus and A. nidulans are the most commonly isolated species. A. nidulans infections are seldom reported in other immunocompromised patients, indicating a unique interaction between this fungus and the CGD host. The occurrence of mucormycosis is mainly noted in the setting of treatment of inflammatory complications with immunosuppressive drugs. Candida infections are infrequently seen and do not cause mucocutaneous disease but do show an age-dependent clinical presentation. The CGD patient is susceptible to a wide range of fungal pathogens, indicating the need to determine the causative fungus, often by invasive diagnostics, to guide optimal and rational treatment. This review summarizes current understanding of invasive fungal infections in patients with CGD and will serve as a starting point to guide optimal treatment strategies and to direct further research aimed at improving outcomes. © Springer Science+Business Media New York 2013.
Opstelten W, Ruijs WLM, Warris A, Binnendijk RSV, Wolfs TFW, Hahné SJM (2013). Klinische les: the measles are here again. Nederlands Tijdschrift voor Geneeskunde, 157(36).
Klinische les: the measles are here again
This supplementary information is presented as submitted by the corresponding author. It has not been copy-edited by NTvG.
Cohen S, Smit C, Van Rossum AMC, Fraaij PLA, Wolfs TFW, Geelen SPM, Schölvinck EH, Warris A, Scherpbier HJ, Pajkrt D, et al (2013). Long-term response to combination antiretroviral therapy in HIV-infected children in the Netherlands registered from 1996 to 2012. AIDS, 27(16), 2567-2575.
Long-term response to combination antiretroviral therapy in HIV-infected children in the Netherlands registered from 1996 to 2012
OBJECTIVES: to describe demographic and treatment characteristics of the Dutch vertically HIV-infected paediatric population from 1996 to 2012, and to investigate the long-term virological and immunological response to combination antiretroviral therapy (cART), with emphasis on the influence of age at cART initiation and initial CD4 cell counts. DESIGN: Descriptive cohort study. METHODS: from 1996 to 2012, all paediatric HIV clinics in the Netherlands provided data on their HIV-infected population. Descriptive statistics, parametric and non-parametric comparative tests, and random-effects linear regression models were performed to investigate the different aspects of this cohort. RESULTS: a total of 229 vertically HIV-infected children were included. The majority of all mothers (64%) and almost half of the children (43%) originated from sub-Saharan Africa. Ritonavir-boosted lopinavir and efavirenz have replaced indinavir, nelfinavir and nevirapine as preferred first-line cART regimens. Long-term CD4 T-cell reconstitution (with CD4 cell counts corrected for age) was independent of age and CD4 cell count at cART initiation. The decline in HIV viral load after cART introduction occurred faster over the studied time period. The percentage of children with an undetectable viral load rose substantially from 1996 to 2012. Mortality was 0.3 per 100 person-years. CONCLUSION: a sustained immunological response in the Dutch paediatric HIV-infected population was independent of age as well as CD4 cell count at cART initiation, despite a higher initial HIV viral load in the youngest children. The percentage of children with an undetectable HIV viral load rose substantially over the years and there was a low mortality rate in comparison with reports from other industrialized countries. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Schoffelen AF, van Lelyveld SFL, Barth RE, Gras L, de Wolf F, Netea MG, Hoepelman AIM (2013). Lower incidence of Pneumocystis jirovecii pneumonia among Africans in the Netherlands host or environmental factors?. AIDS, 27(7), 1179-1184.
Stol K, Verhaegh SJC, Graamans K, Engel JAM, Sturm PDJ, Melchers WJG, Meis JF, Warris A, Hays JP, Hermans PWM, et al (2013). Microbial profiling does not differentiate between childhood recurrent acute otitis media and chronic otitis media with effusion. International Journal of Pediatric Otorhinolaryngology, 77(4), 488-493.
Microbial profiling does not differentiate between childhood recurrent acute otitis media and chronic otitis media with effusion
Objectives: Otitis media (OM) is one of the most frequent diseases of childhood, with a minority of children suffering from recurrent acute otitis media (rAOM) or chronic otitis media with effusion (COME), both of which are associated with significant morbidity. We investigated whether the microbiological profiling could be used to differentiate between these two conditions. Methods: Children up to five years of age, with rAOM (n=45) or COME (n=129) and scheduled for tympanostomy tube insertion were enrolled in a prospective study between 2008 and 2009. Middle ear fluids (n=119) and nasopharyngeal samples (n=173) were collected during surgery for bacterial culture and PCR analysis to identify Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and to detect 15 distinct respiratory viruses. Results: the occurrence of bacterial and viral pathogens in middle ear fluids did not significantly differ between patients suffering from rAOM and COME. In both patient cohorts, H. influenzae and rhinovirus were the predominant pathogens in the middle ear and nasopharynx. Nasopharyngeal carriage with two or three bacterial pathogens was associated with the presence of bacteria in middle ear fluid (P=0.04). The great majority of the bacteria isolated from middle ear fluid were genetically identical to nasopharyngeal isolates from the same patient. Conclusions: Based on these results, we propose that the common perception that rAOM is associated with recurrent episodes of microbiologically mediated AOM, whereas COME is generally a sterile inflammation, should be reconsidered. © 2012 Elsevier Ireland Ltd.
Nooitgedagt JE, Warris A, Liem KD, Van't Hek L, Henriet SS (2013). Pertussis in young infants: a dangerous disease with non-specific signs. Nederlands Tijdschrift voor Geneeskunde, 157(4).
Kinabo GD, Sprengers M, Msuya LJ, Shayo AM, van Asten H, Dolmans WMV, van der Ven AJAM, Warris A (2013). Prevalence of lipodystrophy in HIV-infected children in Tanzania on highly active antiretroviral therapy. Pediatr Infect Dis J, 32(1), 39-44.
Prevalence of lipodystrophy in HIV-infected children in Tanzania on highly active antiretroviral therapy.
OBJECTIVE: Highly active antiretroviral therapy (HAART) has been associated with lipodystrophy (LD) in adults but data are more limited for children. The purpose of this study was to determine the prevalence of and risk factors for LD in Tanzanian children receiving HAART by clinical assessment and to compare the results with anthropometric data. DESIGN AND METHODS: a cross-sectional study was performed in a cohort of HIV-infected children aged 1-18 years receiving HAART in a single center in Moshi, Tanzania. Age, gender, past and current medication regimens and anthropometric measurements were recorded. A clinical scoring method was used to assess LD. Backward binary multivariate logistic regression was used to determine relationships between anthropometric measurements and the presence of clinical LD. RESULTS: Among 210 HIV-infected children, the prevalence of LD was 30% (95% confidence interval [CI]: 23.8-36.2) overall, 19% (95% CI: 13.7-24.3) for lipoatrophy only, 3.8% (95% CI: 1.2-6.4) for lipohypertrophy only and 7.1% (95% CI: 3.6-10.6) for the mixed type. Most cases were mild. Older age and use of stavudine increased the risk of LD. Overall, the study population was stunted but not underweight. In children with relatively lower weight-for-height (
Brand HK, Borm G, Hermans P, Warris A (2013). Response to 12-0176. Pediatric Pulmonology, 48(6), 625-626.
Geelen J, Pfundt R, Meijer J, Verheijen FW, van Kuilenburg ABP, Warris A, Marcelis C (2013). Severe phenotype of severe combined immunodeficiency caused by adenosine deaminase deficiency in a patient with a homozygous mutation due to uniparental disomy. J Allergy Clin Immunol, 132(1), 222-223. Author URL.
Verweij PE, Warris A (2013). Update on antifungal resistance in children: Epidemiology and recommendations. Pediatric Infectious Disease Journal, 32(5), 556-557.
Schatorjé EJH, van der Steeg H, Stelma F, Hebeda K, Warris A (2013). [Borrelial lymphocytoma]. Nederlands tijdschrift voor geneeskunde, 157(52).
[Borrelial lymphocytoma].
Opstelten W, Ruijs WL, Warris A, van Binnendijk RS, Wolfs TFW, Hahné SJM (2013). [The measles are here again]. Nederlands tijdschrift voor geneeskunde, 157(34).
[The measles are here again].
Since the vaccination of Dutch children against the measles through the National Immunisation Programme started in 1976, the incidence of measles has greatly decreased. Local epidemics do still occur, however; these are largely confined to minority groups of orthodox Protestants who object to vaccination on religious grounds. A local epidemic of the measles has been developing in the Netherlands since May of this year, predominantly within unvaccinated groups where the highly contagious virus can easily spread. We describe an unvaccinated 10-year-old boy with an uncomplicated case of the measles and an unvaccinated 9-year-old boy who developed encephalitis as a complication of the measles. From the waning of maternal antibodies until the first regular vaccination and where herd immunity is lacking, children are at risk of the measles. For this reason, an extra (age < 12 months) or early (12-14 months) vaccination is being offered during the current epidemic for all children aged 6 to 14 months who live in areas with low (< 90%) vaccination coverage.
de Groot R, Warris A (2012). 29th ESPID Annual Meeting in the Hague, the Netherlands. Pediatr Infect Dis J, 31(4). Author URL.
Henriet SSV, Verweij PE, Warris A (2012). Aspergillus nidulans and chronic granulomatous disease: a unique host-pathogen interaction. J Infect Dis, 206(7), 1128-1137.
Aspergillus nidulans and chronic granulomatous disease: a unique host-pathogen interaction.
Invasive fungal infections are a major threat for patients suffering from chronic granulomatous disease (CGD), a primary immunodeficiency caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase. Interestingly, Aspergillus (Emericella) nidulans is the second most encountered mold in CGD patients, causing almost exclusively invasive infections in this specific host, and is characterized by its aggressive behavior. A proper diagnosis is complicated by the often mild clinical presentation, the low sensitivity of the currently used diagnostic tools, and the difficulties in accurate identification of the Emericella species. According to the hitherto accepted view on the role of the NADPH-oxidase in the innate host-defense pathway, the pathogenesis of A. nidulans in CGD cannot be explained. This synopsis covers the current understanding of invasive infections caused by A. nidulans in the CGD patient and is intended to direct further research by indicating gaps in our knowledge and to guide optimal management strategies.
Donker AE, Mavinkurve-Groothuis AMC, van Die LE, Verweij PE, Hoogerbrugge PM, Warris A (2012). Favorable outcome of chronic disseminated candidiasis in four pediatric patients with hematological malignancies. Med Mycol, 50(3), 315-319.
Favorable outcome of chronic disseminated candidiasis in four pediatric patients with hematological malignancies.
Four children were diagnosed with chronic disseminated candidiasis (CDC) during treatment for hematological malignancies. All presented with persistent fever, not responsive to broad-spectrum antibiotics, abdominal distension and hepatosplenomegaly. Two children needed artificial ventilation because of respiratory insufficiency. The time between onset of neutropenic fever and diagnosis of CDC ranged from 20-49 days. Ultrasound and computed tomography failed to demonstrate CDC during the neutropenic phase. All children needed a liver or spleen biopsy to establish the diagnosis of CDC. Three of four patients continued chemotherapy during treatment for the fungal infection. All patients had a favorable outcome, both in terms of the invasive Candida infections, as well as their underlying malignancies.
Verhagen LM, Hermans PWM, Warris A, de Groot R, Maes M, Villalba JA, del Nogal B, van den Hof S, Mughini Gras L, van Soolingen D, et al (2012). Helminths and skewed cytokine profiles increase tuberculin skin test positivity in Warao Amerindians. Tuberculosis (Edinb), 92(6), 505-512.
Helminths and skewed cytokine profiles increase tuberculin skin test positivity in Warao Amerindians.
The immune regulatory mechanisms involved in the acquisition of Mycobacterium tuberculosis infection in children are largely unknown. We investigated the influence of parasitic infections, malnutrition and plasma cytokine profiles on tuberculin skin test (TST) positivity in Warao Amerindians in Venezuela. Pediatric household contacts of sputum smear-positive tuberculosis (TB) cases were enrolled for TST, chest radiograph, plasma cytokine analyses, QuantiFERON-TB Gold In-Tube (QFT-GIT) testing and stool examinations. Factors associated with TST positivity were studied using generalized estimation equations logistic regression models. of the 141 asymptomatic contacts, 39% was TST-positive. After adjusting for age, gender and nutritional status, TST positivity was associated with Trichuris trichiura infections (OR 3.5, 95% CI 1.1-11.6) and low circulating levels of T helper 1 (Th1) cytokines (OR 0.51, 95% CI 0.33-0.79). Ascaris lumbricoides infections in interaction with Th2- and interleukin (IL)-10-dominated cytokine profiles were positively associated with TST positivity (OR 3.1, 95% CI 1.1-8.9 and OR 2.4, 95% CI 1.04-5.7, respectively). A negative correlation of QFT-GIT mitogen responses with Th1 and Th2 levels and a positive correlation with age were observed (all p < 0.01). We conclude that helminth infections and low Th1 cytokine plasma levels are significantly associated with TST positivity in indigenous Venezuelan pediatric TB contacts.
Verhagen LM, Warris A, Hermans PWM, del Nogal B, de Groot R, de Waard JH (2012). High prevalence of acute respiratory tract infections among Warao Amerindian children in Venezuela in relation to low immunization coverage and chronic malnutrition. Pediatr Infect Dis J, 31(3), 255-262.
High prevalence of acute respiratory tract infections among Warao Amerindian children in Venezuela in relation to low immunization coverage and chronic malnutrition.
BACKGROUND: Higher prevalence rates of acute respiratory tract infections (ARTIs) have been described in Australian and Canadian indigenous populations than in nonindigenous age-matched counterparts. Few studies on ARTIs in South American indigenous populations have been published. We performed a cross-sectional survey to describe the prevalence of upper respiratory tract infections and acute lower respiratory tract infections (ALRTIs) and associations with malnutrition and immunization status. METHODS: from December 1, 2009 to May 31, 2010, 487 Warao Amerindian children 0 to 59 months of age living in the Delta Amacuro in Venezuela were included in a cross-sectional survey. Data were obtained through parent questionnaires, vaccination cards, and physical examinations including anthropometric measurements. RESULTS: of the 487 children, 47% presented with an ARTI. of these, 60% had upper respiratory tract infections and 40% were ALRTI. Immunization coverage was low, with only 27% of all children presenting a vaccination card being fully immunized. The prevalence of malnutrition was high (52%), with stunting (height-for-age
Zwitserloot AM, Mavinkurve-Groothuis AMC, Galama JM, Verweij PE, Hoogerbrugge PM, Warris A (2012). Importance of neutropenia for development of invasive infections at various phases of treatment for hemato-oncological diseases in children. Scand J Infect Dis, 44(5), 355-362.
Importance of neutropenia for development of invasive infections at various phases of treatment for hemato-oncological diseases in children.
INTRODUCTION: Prolonged neutropenia in patients with acute myeloid leukemia (AML), relapsed acute lymphoblastic leukemia (r-ALL), myelodysplastic syndrome (MDS), and those receiving hematopoietic stem cell transplantation (HSCT), is a well-known risk factor for infectious complications. Few data are available about the incidence and etiology of infectious episodes during the total treatment period associated with a decreased immunity. METHODS: Between January 2000 and December 2005 children diagnosed with AML, r-ALL, and MDS, and post-HSCT patients were included in the study. A retrospective review based on microbiological data was performed to describe the incidence and etiology of the infectious complications during the total treatment period. RESULTS: One hundred and thirty disease-specific patient episodes were included. Forty-two percent of 184 microbiologically proven infectious episodes were diagnosed in patients receiving chemotherapy, and 58% occurred in HSCT patients. During neutropenia, 123 (67%) infectious episodes were diagnosed; of the isolated species 83% were bacterial, 6% fungal, and 11% viral. In the period without neutropenia, 61 (33%) infectious episodes were diagnosed, with 38% bacterial, 3% fungal, and 59% viral species isolated. of the infectious episodes diagnosed in patients treated with an HSCT, 52% (n = 55) occurred in the post-engraftment period. In contrast, in patients treated with chemotherapy, 92% of the infectious episodes were diagnosed during neutropenia. CONCLUSION: the number of proven infectious episodes in post-HSCT patients was not influenced by the presence of neutropenia, while in patients receiving chemotherapy significantly lower numbers of proven infectious episodes were diagnosed outside the neutropenic period.
Brand HK, de Groot R, Galama JMD, Brouwer ML, Teuwen K, Hermans PWM, Melchers WJG, Warris A (2012). Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis. Pediatr Pulmonol, 47(4), 393-400.
Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis.
BACKGROUND: the clinical relevance of parallel detection of multiple viruses by real-time polymerase chain reaction (RT-PCR) remains unclear. This study evaluated the association between the detection of multiple viruses by RT-PCR and disease severity in children with bronchiolitis. METHODS: Children less than 2 years of age with clinical symptoms of bronchiolitis were prospectively included during three winter seasons. Patients were categorized in three groups based on disease severity; mild (no supportive treatment), moderate (supplemental oxygen and/or nasogastric feeding), and severe (mechanical ventilation). Multiplex RT-PCR of 15 respiratory viruses was performed on nasopharyngeal aspirates. RESULTS: in total, 142 samples were obtained. Respiratory Syncytial virus (RSV) was the most commonly detected virus (73%) followed by rhinovirus (RV) (30%). In 58 samples (41%) more than one virus was detected, of which 41% was a dual infection with RSV and RV. In RSV infected children younger than 3 months, disease severity was not associated with the number of detected viruses. Remarkably, in children older than 3 months we found an association between more severe disease and RSV mono-infections. CONCLUSION: Disease severity in children with bronchiolitis is not associated with infection by multiple viruses. We conclude that other factors, such as age, contribute to disease severity to a larger extent.
Stol K, Diavatopoulos DA, Graamans K, Engel JAM, Melchers WJG, Savelkoul HFJ, Hays JP, Warris A, Hermans PWM (2012). Inflammation in the middle ear of children with recurrent or chronic otitis media is associated with bacterial load. Pediatr Infect Dis J, 31(11), 1128-1134.
Inflammation in the middle ear of children with recurrent or chronic otitis media is associated with bacterial load.
BACKGROUND: Viral upper respiratory tract infections have been described as an important factor in the development of otitis media (OM), although it is unclear whether they facilitate bacterial OM or can directly cause OM. To clarify the role of viral infections in OM, we compared the relative contribution of viruses and bacteria with the induction of inflammatory cytokine responses in the middle ear of children suffering from OM. METHODS: Children up to 5 years of age, with recurrent or chronic episodes of OM and scheduled for ventilation tube insertion were enrolled in a prospective study. Middle ear fluids (n = 116) were collected during surgery, and quantitative polymerase chain reaction was performed to detect bacterial and viral otopathogens, that is, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and 15 respiratory viruses. Finally, concentrations of the inflammatory mediators interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17a and tumor necrosis factor-α were determined. RESULTS: Middle ear fluids were clustered into 4 groups, based on the detection of viruses (28%), bacteria (27%), both bacteria and viruses (27%) or no otopathogens (19%). Bacterial detection was associated with significantly elevated concentrations of cytokines compared with middle ear fluids without bacteria (P < 0.001 for all cytokines tested) in a bacterial load-dependent and species-dependent manner. In contrast, the presence of viruses was not associated with changes in cytokine values, and no synergistic effect between viral-bacterial coinfections was observed. CONCLUSIONS: the presence of bacteria, but not viruses, is associated with an increased inflammatory response in the middle ear of children with recurrent or chronic OM.
Smeekens SP, Henriet SSV, Gresnigt MS, Joosten LAB, Hermans PWM, Netea MG, Warris A, van de Veerdonk FL (2012). Low interleukin-17A production in response to fungal pathogens in patients with chronic granulomatous disease. J Interferon Cytokine Res, 32(4), 159-168.
Low interleukin-17A production in response to fungal pathogens in patients with chronic granulomatous disease.
Patients with chronic granulomatous disease (CGD) cannot produce reactive oxygen species (ROS) due to a genetic defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system. Dysregulation of the L-tryptophan metabolism in mice with defects in NADPH oxidase, resulting in overproduction of interleukin (IL)-17, has been proposed to link ROS defects with hyperinflammation and susceptibility to pulmonary aspergillosis. In this study, we assessed the L-tryptophan metabolism and cytokine profiles in response to fungal pathogens in CGD patients. Peripheral blood mononuclear cells (PBMCs) from CGD patients showed increased production of IL-6, tumor necrosis factor-α, and interferon-γ upon stimulation with Aspergillus or Candida species, while IL-17A production was strikingly low compared with healthy controls. Indoleamine 2,3-dioxygenase expression was similar in PBMCs and neutrophils from CGD patients compared with healthy controls. Conversion of L-tryptophan to L-kynurenine, as measured by high-performance liquid chromatography, did not differ between CGD patients and healthy controls. Moreover, adding L-kynurenine to the cell cultures did not suppress fungal-induced IL-17A production. Although PBMCs of CGD patients produced more proinflammatory cytokines after stimulation, IL-17A production was strikingly low in response to fungal pathogens when compared with healthy controls. In addition, cells from CGD patients did not display a defective L-tryptophan metabolism.
Verhagen LM, López D, Hermans PWM, Warris A, de Groot R, García JF, de Waard JH, Aarnoutse RE (2012). Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations. Trop Med Int Health, 17(12), 1449-1456.
Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations.
OBJECTIVES: the World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. METHODS: Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined. RESULTS: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01). CONCLUSION: We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.
Verhagen MMM, Last JI, Hogervorst FBL, Smeets DFCM, Roeleveld N, Verheijen F, Catsman-Berrevoets CE, Wulffraat NM, Cobben JM, Hiel J, et al (2012). Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study. Hum Mutat, 33(3), 561-571.
Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.
Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk.
Steinbach WJ, Roilides E, Berman D, Hoffman JA, Groll AH, Bin-Hussain I, Palazzi DL, Castagnola E, Halasa N, Velegraki A, et al (2012). Results from a prospective, international, epidemiologic study of invasive candidiasis in children and neonates. Pediatr Infect Dis J, 31(12), 1252-1257.
Results from a prospective, international, epidemiologic study of invasive candidiasis in children and neonates.
BACKGROUND: Candida species are the third most common cause of pediatric health care-associated bloodstream infection in the United States and Europe. To our knowledge, this report from the International Pediatric Fungal Network is the largest prospective, multicenter observational study dedicated to pediatric and neonatal invasive candidiasis. METHODS: from 2007 to 2011, we enrolled 196 pediatric and 25 neonatal patients with invasive candidiasis. RESULTS: Non-albicans Candida species predominated in pediatric (56%) and neonatal (52%) age groups, yet Candida albicans was the most common species in both groups. Successful treatment responses were observed in pediatric (76%) and neonatal patients (92%). Infection with Candida parapsilosis led to successful responses in pediatric (92%) and neonatal (100%) patients, whereas infection with Candida glabrata was associated with a lower successful outcome in pediatric patients (55%). The most commonly used primary antifungal therapies for pediatric invasive candidiasis were fluconazole (21%), liposomal amphotericin B (20%) and micafungin (18%). Outcome of pediatric invasive candidiasis was similar in response to polyenes (73%), triazoles (67%) and echinocandins (73%). The most commonly used primary antifungal therapies for neonatal invasive candidiasis were fluconazole (32%), caspofungin (24%) and liposomal amphotericin B (16%) and micafungin (8%). Outcomes of neonatal candidiasis by antifungal class again revealed similar response rates among the classes. CONCLUSIONS: We found a predominance of non-albicans Candida infection in children and similar outcomes based on antifungal class used. This international collaborative study sets the foundation for large epidemiologic studies focusing on the unique features of neonatal and pediatric candidiasis and comparative studies of therapeutic interventions in these populations.
Brand KH, Ahout IML, de Groot R, Warris A, Ferwerda G, Hermans PWM (2012). Use of MMP-8 and MMP-9 to assess disease severity in children with viral lower respiratory tract infections. J Med Virol, 84(9), 1471-1480.
Use of MMP-8 and MMP-9 to assess disease severity in children with viral lower respiratory tract infections.
Matrix metalloproteinases (MMPs) play an important role in respiratory inflammatory diseases, such as asthma and chronic obstructive pulmonary disease. It was hypothesized that MMP-8 and MMP-9 may function as biological markers to assess disease severity in viral lower respiratory tract infections in children. MMP-8 and MMP-9 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) and granulocytes obtained in both the acute and recovery phase from 153 children with mild, moderate, and severe viral lower respiratory tract infections were determined using real-time PCR. In addition, MMP-8 and MMP-9 concentrations in blood and nasopharyngeal specimens were determined during acute mild, moderate, and severe infection, and after recovery using ELISA. Furthermore, PBMCs and neutrophils obtained from healthy volunteers were stimulated with RSV, LPS (TLR4 agonist), and Pam3Cys (TLR2 agonist) in vitro. Disease severity of viral lower respiratory tract infections in children is associated with increased expression levels of the MMP-8 and MMP-9 genes in both PBMCs and granulocytes. On the contrary, in vitro experiments showed that MMP-8 and MMP-9 mRNA and protein expression in PBMCs and granulocytes is not induced by stimulation with RSV, the most frequent detected virus in young children with viral lower respiratory tract infections. These data indicate that expression levels of the MMP-8 and MMP-9 genes in both PBMCs and neutrophils are associated with viral lower respiratory tract infections disease severity. These observations justify future validation in independent prospective study cohorts of the usefulness of MMP-8 and MMP-9 as potential markers for disease severity in viral respiratory infections.
Hartwig NG, Warris A, van de Vosse E, van der Zanden AGM, Schülin-Casonato T, van Ingen J, van Hest R (2011). "Mycobacterium tilburgii" infection in two immunocompromised children: importance of molecular tools in culture-negative mycobacterial disease diagnosis. J Clin Microbiol, 49(12), 4409-4411.
"Mycobacterium tilburgii" infection in two immunocompromised children: importance of molecular tools in culture-negative mycobacterial disease diagnosis.
"Mycobacterium tilburgii" is a nontuberculous mycobacterium that cannot be cultured by current techniques. It is described as causing disseminated disease in adults. We present the first cases of disseminated disease in 2 immunocompromised children. This paper stresses the importance of molecular techniques for correct mycobacterial identification and guidance to immunological diagnosis.
Welzen MEB, Brüggemann RJM, Van Den Berg JM, Voogt HW, Gilissen JH, Pajkrt D, Klein N, Burger DM, Warris A (2011). A novel twice daily posaconazole dosing algorithm for children with chronic granulomatous disease results in adequate exposure. Pharmaceutisch Weekblad, 146(50), 211-214.
Welzen MEB, Brüggemann RJM, Van Den Berg JM, Voogt HW, Gilissen JH, Pajkrt D, Klein N, Burger DM, Warris A (2011). A twice daily posaconazole dosing algorithm for children with chronic granulomatous disease. Pediatr Infect Dis J, 30(9), 794-797.
A twice daily posaconazole dosing algorithm for children with chronic granulomatous disease.
Posaconazole (PSZ) may be an attractive alternative for antifungal prophylaxis in children with chronic granulomatous disease. Experience with PSZ in pediatric patients is limited, and no specific dose recommendations exist. A twice daily dosing algorithm based on allometric scaling (body-weight based) for PSZ results in adequate exposure and appears to be safe in children with chronic granulomatous disease.
Ijspeert H, Lankester AC, van den Berg JM, Wiegant W, van Zelm MC, Weemaes CMR, Warris A, Pan-Hammarström Q, Pastink A, van Tol MJD, et al (2011). Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide. Genes Immun, 12(6), 434-444.
Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide.
Artemis deficiency is known to result in classical T-B- severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical T-B- SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5' splice-site or an intronic point mutation creating a novel 3' splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3' splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.
Van Der Linden JWM, Warris A, Verweij PE (2011). Aspergillus species intrinsically resistant to antifungal agents. Med Mycol, 49 Suppl 1, S82-S89.
Aspergillus species intrinsically resistant to antifungal agents.
Polyphasic taxonomy has had a major impact on the species concept of the genus Aspergillus. New sibling species have been described that exhibit in vitro susceptibility profiles that differ significantly from that of Aspergillus fumigatus. While acquired resistance is an emerging problem in A. fumigatus, non-A. fumigatus Aspergillus species may be intrinsically resistant to specific classes of antifungal agents. Minimum inhibitory concentrations of amphotericin B and azoles for some of the non-A. fumigatus Aspergillus species are elevated compared to A. fumigatus. Furthermore, the clinical presentation and evolution of invasive infections caused by these species may differ from that commonly observed for A. fumigatus. As the role of the newly identified Aspergillus species in causing invasive aspergillosis remains unclear, surveillance networks that incorporate sequence-based identification of clinical isolates are needed to determine the species distribution, the clinical disease and outcome of patients with invasive aspergillosis. Preclinical and clinical studies are needed to further improve the methods for in vitro susceptibility testing and to investigate the impact of elevated MICs on antifungal drug efficacy.
Driessen GJ, van Zelm MC, van Hagen PM, Hartwig NG, Trip M, Warris A, de Vries E, Barendregt BH, Pico I, Hop W, et al (2011). B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency. Blood, 118(26), 6814-6823.
B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency.
Common variable immunodeficiency disorder (CVID) is the most prevalent form of primary idiopathic hypogammaglobulinemia. Identification of genetic defects in CVID is hampered by clinical and immunologic heterogeneity. By flow cytometric immunophenotyping and cell sorting of peripheral B-cell subsets of 37 CVID patients, we studied the B-cell compartment at the B-cell subset level using the κ-deleting recombination excision circle assay to determine the replication history and the Igκ-restriction enzyme hot-spot mutation assay to assess the somatic hypermutation status. Using this approach, 5 B-cell patterns were identified, which delineated groups with unique replication and somatic hypermutation characteristics. Each B-cell pattern reflected an immunologically homogenous patient group for which we proposed a different pathophysiology: (1) a B-cell production defect (n = 8, 18%), (2) an early peripheral B-cell maturation or survival defect (n = 4, 11%), (3) a B-cell activation and proliferation defect (n = 12, 32%), (4) a germinal center defect (n = 7, 19%), and (5) a postgerminal center defect (n = 6, 16%). The results of the present study provide for the first time insight into the underlying pathophysiologic background in 5 immunologically homogenous groups of CVID patients. Moreover, this study forms the basis for larger cohort studies with the defined homogenous patient groups and will facilitate the identification of underlying genetic defects in CVID.
Henriet SSV, Hermans PWM, Verweij PE, Simonetti E, Holland SM, Sugui JA, Kwon-Chung KJ, Warris A (2011). Human leukocytes kill Aspergillus nidulans by reactive oxygen species-independent mechanisms. Infect Immun, 79(2), 767-773.
Human leukocytes kill Aspergillus nidulans by reactive oxygen species-independent mechanisms.
Invasive aspergillosis is a major threat for patients suffering from chronic granulomatous disease (CGD). Although Aspergillus fumigatus is the most commonly encountered Aspergillus species, the presence of A. nidulans appears to be disproportionately high in CGD patients. The purpose of this study was to investigate the involvement of the NADPH oxidase and the resulting reactive oxygen species (ROS) in host defense against fungi and to clarify their relationship toward A. nidulans. Murine CGD alveolar macrophages (AM) and polymorphonuclear leukocytes (PMN) and peripheral blood mononuclear cells (PBMC) from healthy controls and CGD patients were challenged with either A. fumigatus or A. nidulans. Analysis of the antifungal effects of ROS revealed that A. nidulans, in contrast to A. fumigatus, is not susceptible to ROS. In addition, infection with live A. nidulans did not result in any measurable ROS release. Remarkably, human CGD PMN and PBMC and murine CGD AM were at least equipotent at arresting conidial germination compared to healthy controls. Blocking of the NADPH oxidase resulted in significantly reduced damage of A. fumigatus but did not affect A. nidulans hyphae. Furthermore, the microbicidal activity of CGD PMN was maintained toward A. nidulans but not A. fumigatus. In summary, antifungal resistance to A. nidulans is not directly ROS related. The etiology of A. nidulans infections in CGD cannot be explained by the simple absence of the direct microbicidal effect of ROS. In vivo, the NADPH oxidase is a critical regulator of innate immunity whose unraveling will improve our understanding of fungal pathogenesis in CGD.
Brüggemann RJM, van der Linden JWM, Verweij PE, Burger DM, Warris A (2011). Impact of therapeutic drug monitoring of voriconazole in a pediatric population. Pediatr Infect Dis J, 30(6), 533-534.
Impact of therapeutic drug monitoring of voriconazole in a pediatric population.
Voriconazole trough concentrations more than 1 mg/L are associated with a higher likelihood of success. It is unknown whether these trough concentrations are reached with the current recommended pediatric dosing schedule. We retrospectively analyzed the results of our therapeutic drug monitoring service for voriconazole in 18 children treated at our children's hospital. Thirty-nine voriconazole plasma concentrations were measured. In 44% of patients, the first voriconazole concentration was below the target. Dose adjustment eventually resulted in plasma concentrations within the predefined target range in all patients. Given the high proportion of patients with subtherapeutic concentrations, monitoring plasma concentrations should be performed routinely in pediatric patients receiving voriconazole.
Lutsar I, Trafojer UMT, Heath PT, Metsvaht T, Standing J, Esposito S, de Cabre VM, Oeser C, Aboulker J-P (2011). Meropenem vs standard of care for treatment of late onset sepsis in children of less than 90 days of age: study protocol for a randomised controlled trial. Trials, 12(1).
Delsing CE, Warris A, Bleeker-Rovers CP (2011). Q fever: still more queries than answers. Adv Exp Med Biol, 719, 133-143.
Q fever: still more queries than answers.
Q fever is a worldwide zoonosis, caused by C. burnetii. Infection usually occurs through inhalation of infected aerosols. The reservoir mainly consists of dairy cattle. Clinical symptoms of acute Q fever are non-specific and resemble a mild flu-like illness. Children often present with gastrointestinal symptoms and rash. Rarely, chronic infection develops. This is usually manifested as endo-carditis, vascular infection and, in children, osteomyelitis. Diagnosis is based on serology and nucleic acid amplification (PCR). Doxycycline is the treatment of choice for acute infection. An alternative for young children and pregnant women is cotrimoxazole. Chronic infection requires long term treatment usually with doxycycline combined with hydroxychloroquine.
van de Glind GJ, Gidding CEM, Verlaat CMW, Duthoi K, Backx APC, Verweij PE, Warris A (2010). Acute Cardiac Failure due to Intra-Atrial Mass Caused by Zygomycetes in an Immunocompromised Paediatric Patient. Case Rep Med, 2010
Acute Cardiac Failure due to Intra-Atrial Mass Caused by Zygomycetes in an Immunocompromised Paediatric Patient.
Cardiac zygomycosis can be a critical condition with sudden onset of severe congestive heart failure followed by severe hemodynamic deterioration. We report a fatal course of disseminated fungal infection with a massive intra-atrial thrombosis caused by a zygomycete, in a five year old boy treated for acute lymphoblastic leukaemia. In addition, we discuss the literature concerning infections caused by zygomycetes involving the heart. Prognosis is poor. A high index of suspicion and an aggressive diagnostic and therapeutic approach with the prompt start of preemptive antifungal therapy are key factors to improve outcome.
Chai LYA, Netea MG, Sugui J, Vonk AG, van de Sande WWJ, Warris A, Kwon-Chung KJ, Kullberg BJ (2010). Aspergillus fumigatus conidial melanin modulates host cytokine response. Immunobiology, 215(11), 915-920.
Aspergillus fumigatus conidial melanin modulates host cytokine response.
Melanin biopigments have been linked to fungal virulence. Aspergillus fumigatus conidia are melanised and are weakly immunogenic. We show that melanin pigments on the surface of resting Aspergillus fumigatus conidia may serve to mask pathogen-associated molecular patterns (PAMPs)-induced cytokine response. The albino conidia induced significantly more proinflammatory cytokines in human peripheral blood mononuclear cells (PBMC), as compared to melanised wild-type conidia. Blocking dectin-1 receptor, Toll-like receptor 4 or mannose receptor decreased cytokine production induced by the albino but not by the wild type conidia. Moreover, albino conidia stimulated less potently, cytokine production in PBMC isolated from an individual with defective dectin-1, compared to the stimulation of cells isolated from healthy donors. These results suggest that β-glucans, but also other stimulatory PAMPs like mannan derivatives, are exposed on conidial surface in the absence of melanin. Melanin may play a modulatory role by impeding the capability of host immune cells to respond to specific ligands on A. fumigatus.
Verhagen LM, Warris A, van Soolingen D, de Groot R, Hermans PWM (2010). Human immunodeficiency virus and tuberculosis coinfection in children: challenges in diagnosis and treatment. Pediatr Infect Dis J, 29(10), e63-e70.
Human immunodeficiency virus and tuberculosis coinfection in children: challenges in diagnosis and treatment.
The burden of childhood tuberculosis (TB) is influenced by the human immunodeficiency virus (HIV) epidemic and this dangerous synergy affects various aspects of both diseases; from pathogenesis and the epidemiologic profile to clinical presentation, diagnosis, treatment, and prevention. HIV-infected infants and children are at increased risk of developing severe forms of TB. The TB diagnosis is complicated by diminished sensitivity and specificity of clinical features and diagnostic tools like the tuberculin skin test and chest x-ray. Although alternative ways of pulmonary sampling and the development of interferon-γ assays have shown to lead to some improvement of TB diagnosis in HIV-infected children, new diagnostic tools are urgently needed. Coadministration of anti-TB treatment and antiretroviral drugs induces severe complications, and this highlights the need to define optimal treatment regimens. Practical implementation of these regimens in TB control programs should be combined with isoniazid preventive therapy in TB-exposed HIV-infected children. The risk of severe complications after Bacille Calmette-Guérin vaccination of HIV-infected children emphasizes the need for new nonviable vaccines. This article reviews the current status of pediatric HIV-TB coinfection with specific emphasis on the diagnosis and treatment.
Damen GM, van Krieken JH, Hoppenreijs E, van Os E, Tolboom JJM, Warris A, Yntema J-B, Nieuwenhuis EES, Escher JC (2010). Overlap, common features, and essential differences in pediatric granulomatous inflammatory bowel disease. J Pediatr Gastroenterol Nutr, 51(6), 690-697.
Overlap, common features, and essential differences in pediatric granulomatous inflammatory bowel disease.
Overlap in the clinical presentation of pediatric granulomatous inflammatory bowel disease may be substantial, depending on the mode of presentation. Chronic granulomatous disease (CGD) may present with granulomatous colitis, perianal abscesses, hepatic abscesses or granulomas, failure to thrive, and obstruction of the gastrointestinal tract (including esophageal strictures and dysmotility, delayed gastric emptying, and small bowel obstruction). Anemia, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, and hypoalbuminemia are nonspecific and may occur in any of the granulomatous inflammatory bowel diseases. In histology, macrophages with cytoplasmic inclusions will be rather specific for CGD. Sarcoidosis may present with abdominal pain or discomfort, diarrhea, weight loss, growth failure, delayed puberty, erythema nodosum, arthritis, uveitis, and hepatic granulomata. Only in 55% of the patients will angiotensin-converting enzyme be elevated. The noncaseating epithelioid granulomata will be unspecific. Bronchoalveolar lymphocytosis and abnormalities in pulmonary function are reported in sarcoidosis and in Crohn disease (CD) and CGD. Importantly, patients with CD may present with granulomatous lung disease, fibrosing alveolitis, and drug-induced pneumonitis. Sarcoidosis and concomitant gastrointestinal CD have been reported in patients, as well as coexistence of CD and sarcoidosis in siblings. Common susceptibility loci have been identified in CD and sarcoidosis. CD and CGD share defects in the defense mechanisms against different microbes. In the present review, common features and essential differences are discussed in clinical presentation and diagnostics--including histology--in CGD, sarcoidosis, and CD, together with 2 other granulomatous inflammatory bowel diseases, namely abdominal tuberculosis and Hermansky-Pudlak syndrome. Instructions for specific diagnosis and respective treatments are provided.
Warris A, Onken A, Gaustad P, Janssen W, van der Lee H, Verweij PE, Abrahamsen TG (2010). Point-of-use filtration method for the prevention of fungal contamination of hospital water. J Hosp Infect, 76(1), 56-59.
Point-of-use filtration method for the prevention of fungal contamination of hospital water.
Published data implicate hospital water as a potential source of opportunistic fungi that may cause life-threatening infections in immunocompromised patients. Point-of-care filters are known to retain bacteria, but little is known about their efficacy in reducing exposure to moulds. We investigated the effect of point-of-use filters (Pall-Aquasafe) on the level of contamination of Aspergillus fumigatus and other filamentous fungi. The point-of-use filters were applied to several outlets (taps and showers) on the paediatric bone marrow transplantation (BMT) unit of the National Hospital in Oslo, Norway. In addition the efficacy was investigated using a test rig. The laboratory experiments showed that the filters were highly effective in reducing the number of colony-forming units for a period of at least 15 days. In the BMT unit the filters eliminated the fungi from the water on day 1 but due to particles present in the water the filters occluded, which prevented further evaluations. Our results show that point-of-use filtration might be an effective preventive measure to eliminate filamentous fungi at individual points of water use, thereby reducing patients' exposure.
Smyth AR, Barbato A, Beydon N, Bisgaard H, de Boeck K, Brand P, Bush A, Fauroux B, de Jongste J, Korppi M, et al (2010). Respiratory medicines for children: current evidence, unlicensed use and research priorities. Eur Respir J, 35(2), 247-265.
Respiratory medicines for children: current evidence, unlicensed use and research priorities.
This European Respiratory Society task force has reviewed the evidence for paediatric medicines in respiratory disease occurring in adults and children. We describe off-licence use, research priorities and ongoing studies. Off-licence and off-label prescribing in children is widespread and potentially harmful. Research areas in asthma include novel formulations and regimens, and individualised prescribing. In cystic fibrosis, future studies will focus on screened infants and robust outcome measures are needed. Other areas include new enzyme and antibiotic formulations and the basic defect. Research into pneumonia should include evaluation of new antibacterials and regimens, rapid diagnostic tests and, in pleural infection, antibiotic penetration, fibrinolytics and surveillance. In uncommon conditions, such as primary ciliary dyskinesia, congenital pulmonary abnormalities or neuromuscular disorders, drugs indicated for other conditions (e.g. dornase alfa) are commonly used and trials are needed. In neuromuscular disorders, the beta-agonists may enhance muscle strength and are in need of evaluation. Studies of antibiotic prophylaxis, immunoglobulin and antifungal drugs are needed in immune deficiency. We hope that this summary of the evidence for respiratory medicines in children, highlighting gaps and research priorities, will be useful for the pharmaceutical industry, the paediatric committee of the European Medicines Agency, academic investigators and the lay public.
Boer K, Smit C, van der Flier M, de Wolf F (2010). The comparison of the performance of two screening strategies identifying newly-diagnosed HIV during pregnancy. The European Journal of Public Health, 21(5), 632-637.
Noordzij JG, Wulffraat NM, Haraldsson A, Meyts I, van't Veer LJ, Hogervorst FBL, Warris A, Weemaes CMR (2009). Ataxia-telangiectasia patients presenting with hyper-IgM syndrome. Arch Dis Child, 94(6), 448-449.
Ataxia-telangiectasia patients presenting with hyper-IgM syndrome.
Ataxia-telangiectasia (A-T) is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency (decreased serum IgG subclass and/or IgA levels and lymphopenia). However, 10% of A-T patients present with decreased serum IgG and IgA with normal or raised IgM levels. As cerebellar ataxia and oculocutaneous telangiectasias are not present at very young age, these patients are often erroneously diagnosed as hyper IgM syndrome (HIGM). Eight patients with A-T, showing serum Ig levels suggestive of HIGM on first presentation, are described. All had decreased numbers of T lymphocytes, unusual in HIGM. The diagnosis A-T was confirmed by raised alpha-fetoprotein levels in all patients. To prevent mistaking A-T patients for HIGM it is proposed to add DNA repair disorders as a possible cause of HIGM.
Van Der Linden JW, Warris A, Van Der Meer JW, Bresters D, Melchers WJ, Verweij PE (2009). Azole resistant invasive aspergillosis. Nederlands Tijdschrift voor Geneeskunde, 153(51), 2482-2488.
Chai LYA, Kullberg BJ, Vonk AG, Warris A, Cambi A, Latgé J-P, Joosten LAB, van der Meer JWM, Netea MG (2009). Modulation of Toll-like receptor 2 (TLR2) and TLR4 responses by Aspergillus fumigatus. Infect Immun, 77(5), 2184-2192.
Modulation of Toll-like receptor 2 (TLR2) and TLR4 responses by Aspergillus fumigatus.
Toll-like receptor (TLR)-based signaling pathways in the host may be modulated by pathogens during the course of infection. We describe a novel immunomodulatory mechanism in which Aspergillus fumigatus conidia induce attenuation of TLR2- and TLR4-mediated interleukin (IL)-6 and IL-1beta proinflammatory responses in human mononuclear cells with suppression of IL-1beta mRNA transcription. Background TLR2 and TLR4 mRNA transcription was not influenced. A. fumigatus conidia induced TLR2 internalization and uptake into the phagosome with a resultant decrease in surface receptor expression. A. fumigatus hyphae, on the other hand, selectively downregulated the TLR4-mediated response. These novel immunosuppressive effects may facilitate the invasiveness of A. fumigatus.
van Raam BJ, van Bruggen R, Tool ATJ, Jansen MH, Warris A, Jolles S, Kuijpers TW (2009). Nuclear factor-{kappa}B is not essential for NADPH oxidase activity in neutrophils from anhidrotic ectodermal dysplasia patients. Blood, 113(21), 5362-5363. Author URL.
Zhang X, Pang Q (2009). Response: Homing defect in hematopoietic cells from Fanconi anemia patients. Blood, 113(21), 5362-5362.
Mocroft A, Sterne JAC, Egger M, May M, Grabar S, Furrer H, Sabin C, Fatkenheuer G, Justice A, Reiss P, et al (2009). Variable Impact on Mortality of AIDS-Defining Events Diagnosed during Combination Antiretroviral Therapy: Not all AIDS-Defining Conditions Are Created Equal. Clinical Infectious Diseases, 48(8), 1138-1151.
Variable Impact on Mortality of AIDS-Defining Events Diagnosed during Combination Antiretroviral Therapy: Not all AIDS-Defining Conditions Are Created Equal
Background. The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy. Methods. We analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in
van der Linden JW, Warris A, van der Meer JW, Bresters D, Melchers WJ, Verweij PE (2009). [Azole-resistant invasive aspergillosis]. Ned Tijdschr Geneeskd, 153
[Azole-resistant invasive aspergillosis].
Invasive aspergillosis caused by medical triazole-resistant Aspergillus fumigatus is described in two patients. A 31-year-old male with chronic granulomatous disease developed pulmonary aspergillosis despite itraconazole prophylaxis. A. fumigatus was cultured from the lung and was found to be azole-resistant. The patient was successfully treated with caspofungin. The second patient was a 13-year-old boy with acute lymphoid leukaemia. He developed pulmonary aspergillosis that failed to respond to voriconazole therapy. The infection spread to the brain and an azole-resistant isolate was cultured from a lung biopsy. Despite a switch to liposomal amphotericin B in combination with caspofungin, the infection progressed and the patient died. Azole-resistance has emerged in A. fumigatus and may develop through the treatment of patients. However, there is evidence that in the Netherlands, resistance might be emerging through fungal exposure to azole fungicides. Azole resistance further complicates the management of invasive aspergillosis and should be considered as cause for treatment failure.
Kroft EBM, Melchers WJG, Blokx WAM, de Hoop D, Warris A (2008). A generalized skin eruption in a human immunodeficiency virus-infected boy. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 22(7), 896-897. Author URL.
Groeneveld S, Verweij PE, Van't Hek L, Bokkerink JPM, Warris A (2008). Amphotericin B-deoxycholate overdose due to administration error in pediatric patients. MEDICAL MYCOLOGY, 46(2), 185-187. Author URL.
D'Hauw A, Seyger MMB, Groenen PJTA, Weemaes CMR, Warris A, Blokx WAM (2008). Cutaneous graft-versus-host-like histology in childhood. Importance of clonality analysis in differential diagnosis. A case report. BRITISH JOURNAL OF DERMATOLOGY, 158(5), 1153-1156. Author URL.
Zwitserloot AM, Warris A, van't Hek LG, van Die LE, Verweij PE, Mavinkurve-Groothuis AMC (2008). Disseminated aspergillosis in an adolescent with acute lymphoblastic leukemia. PEDIATRIC BLOOD & CANCER, 51(3), 423-426. Author URL.
(2008). Does short-term virologic failure translate to clinical events in antiretroviral-naïve patients initiating antiretroviral therapy in clinical practice?. AIDS, 22(18), 2481-2492.
Verweij PE, Varga J, Houbraken J, Rijs AJMM, VerduynLunel FM, Blijlevens NMA, Shea YR, Holland SM, Warris A, Melchers WJG, et al (2008). Emericella quadrilineata as cause of invasive aspergillosis. EMERGING INFECTIOUS DISEASES, 14(4), 566-572. Author URL.
Dekkers R, Verweij PE, Weemaes CMR, Severijnen RSVM, Van Krieken JHJM, Warris A (2008). Gastrointestinal zygomycosis due to Rhizopus microsporus var. rhizopodiformis as a manifestation of chronic granulomatous disease. MEDICAL MYCOLOGY, 46(5), 491-494. Author URL.
de Jager M, Blokx W, Warris A, Bergers M, Link M, Weemaes C, Seyger M (2008). Immunohistochemical features of cutaneous granulomas in primary immunodeficiency disorders: a comparison with cutaneous sarcoidosis. JOURNAL OF CUTANEOUS PATHOLOGY, 35(5), 467-472. Author URL.
Mennink-Kersten MASH, Ruegebrink D, Klont RR, Warris A, Blijlevens NAA, Donnelly JP, Verweij PE (2008). Improved detection of circulating Aspergillus antigen by use of a modified pretreatment procedure. JOURNAL OF CLINICAL MICROBIOLOGY, 46(4), 1391-1397. Author URL.
Verweij PE, Van Der Velden WJFM, Blijlevens NMA, Donnelly JP, Warris A (2008). Invasive zygomycosis in patients treated for haematological malignancies. Nederlands Tijdschrift voor Geneeskunde, 152(5).
Bruggemann RJM, Donnelly JP, Aarnoutse RE, Warris A, Blijlevens NMA, Mouton JW, Verweij PE, Burger DM (2008). Therapeutic drug monitoring of voriconazole. THERAPEUTIC DRUG MONITORING, 30(4), 403-411. Author URL.
Brüggemann RJM, Antonius T, Heijst AV, Hoogerbrugge PM, Burger DM, Warris A (2008). Therapeutic drug monitoring of voriconazole in a child with invasive aspergillosis requiring extracorporeal membrane oxygenation. Ther Drug Monit, 30(6), 643-646.
Therapeutic drug monitoring of voriconazole in a child with invasive aspergillosis requiring extracorporeal membrane oxygenation.
We describe a patient with invasive pulmonary aspergillosis on extracorporeal membrane oxygenation therapy in which therapeutic drug monitoring and individualization of therapy by measuring voriconazole plasma concentrations were performed.
L'homme R, Warris A, Gibb D, Burger D (2007). Children with HIV are not small adults: what is different in pharmacology?. Curr Opin HIV AIDS, 2(5), 405-409.
Children with HIV are not small adults: what is different in pharmacology?
PURPOSE OF REVIEW: the pharmacokinetics of antiretroviral drugs are highly variable among HIV-infected children. This review describes pharmacokinetic processes in children and recent pharmacokinetic data in children with HIV. The general lack of pharmacokinetic data and the potential role of therapeutic drug monitoring are discussed. RECENT FINDINGS: it was found unexpectedly that exposure to lopinavir is decreased in the first 6 months of life. Recent findings of subtherapeutic efavirenz concentrations in children suggest that pediatric dose recommendations should be re-evaluated. In addition, recommended dosing of lamivudine leads to lower exposure in children younger than 6 years of age. Preliminary results of pediatric fixed-dose combination tablets for HIV-infected children with a higher nevirapine to stavudine and lamivudine ratio than adult fixed-dose combinations suggest adequate drug exposure. As an alternative to plasma sampling, concentrations of nevirapine can be determined in saliva. SUMMARY: There is a shortage of pharmacokinetic data in the highly variable population of HIV-infected children. Selected pharmacology studies should be undertaken to improve pediatric dose guidance of existing antiretroviral drugs. Therapeutic drug monitoring is a useful tool to optimize treatment in HIV-infected children. More data are needed, however, to establish child-specific reference values.
Ament AJH, Hubben MWA, Verweij PE, de Groot R, Warris A, Donnelly JP, 't Wout JV, Severens JL (2007). Economic evaluation of targeted treatments of invasive aspergillosis in adult haematopoietic stem cell transplant recipients in the Netherlands: a modelling approach. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 60(2), 385-393. Author URL.
Raaijmakers R, Schroder C, Monnens L, Cornelissen E, Warris A (2007). Fungal peritonitis in children on peritoneal dialysis. PEDIATRIC NEPHROLOGY, 22(2), 288-293. Author URL.
L'homme RFA, Dijkema T, Warris A, van der Ven AJAM, Gibb DM, Burger DM (2007). Pharmacokinetics of two generic fixed-dose combinations for HIV-infected children (Pedimune Baby & Pedimune Junior) are similar to the branded products in healthy adults. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 59(1), 92-96. Author URL.
Verweel G, Burger DM, Sheehan NL, Bergshoeff AS, Warris A, van der Knaap LC, Driessen G, de Groot R, Hartwig NG (2007). Plasma concentrations of the HIV-protease inhibitor lopinavir are suboptimal in children aged 2 years and below. ANTIVIRAL THERAPY, 12(4), 453-458. Author URL.
Winn RM, Warris A, Gaustad P, Abrahamsen TG (2007). The effect of antifungal agents and human monocytes on in vitro galactomannan release by Aspergillus spp. in liquid culture medium. APMIS, 115(12), 1364-1369. Author URL.
Verweij PE, van der Velden WJFM, Donnelly JP, Blijlevens NMA, Warris A (2007). [Invasive zygomycosis in patients treated for haematological malignancies]. Ned Tijdschr Geneeskd, 151(47), 2597-2602.
[Invasive zygomycosis in patients treated for haematological malignancies].
A 52-year-old man underwent haematopoietic stem-cell transplant for myelodysplastic syndrome; after treatment with voriconazole for invasive aspergillosis, he was diagnosed with invasive zygomycosis caused by Rhizopus microsporus. He died despite treatment with intravenous liposomal amphotericin B and posaconazole. A 5-year-old boy with acute lymphatic leukaemia was diagnosed with invasive zygomycosis at autopsy. In a third case, a 16-year-old boy with acute myeloid leukaemia received repeated courses of empiric antifungal therapy, although the presence of an invasive fungal infection was not demonstrated. The patient died, and disseminated invasive zygomycosis caused by Rhizomucor pusillus was found at autopsy. Invasive infections by Zygomycetes are difficult to diagnose and are associated with a high mortality rate. The incidence of invasive zygomycosis appears to be increasing. Therefore, awareness of this type of invasive fungal infection is warranted. Lipid formulations ofamphotericin B remain the first choice for therapy.
Mennink-Kersten MASH, Warris A, Verweij PE (2006). 1,3-beta-D-glucan in patients receiving intravenous amoxicillin-clavulanic acid. NEW ENGLAND JOURNAL OF MEDICINE, 354(26), 2834-2835. Author URL.
Raaijmakers R, Monnens LAH, Warris A, Schroeder CH (2006). Intestinal perforations in children on peritoneal dialysis. PERITONEAL DIALYSIS INTERNATIONAL, 26(6), 712-714. Author URL.
van der Meer W, Stephen Scott C, Verlaat C, Gunnewiek JK, Warris A (2006). Measurement of neutrophil membrane CD64 and HLA-Dr in a patient with abdominal sepsis. J Infect, 53(1), e43-e46.
Measurement of neutrophil membrane CD64 and HLA-Dr in a patient with abdominal sepsis.
A patient with abdominal sepsis, had both intra and extracellular bacteria in a blood smear, and high levels of neutrophil membrane CD64 and HLA-Dr. Intracellular bacteria are only observed in the terminal phase of a sepsis. Our patient recovered, suggesting that a high expression of neutrophil CD64 is indicative for a good prognosis.
Wortmann SB, Fiselier TJW, Van de Kar NCAJ, Aarts RAHM, Warris A, Draaisma JMT (2006). Refractory severe intestinal vasculitis due to Henoch-Schonlein Purpura: Successful treatment with plasmapheresis. ACTA PAEDIATRICA, 95(5), 622-623. Author URL.
De Mol AC, Vrancken S, Eggink AJ, Verduyn Lunel FM, Warris A (2006). Rubella epidemic in the Netherlands in 2004/'05: First newborn with congenital rubella syndrome. Nederlands Tijdschrift voor Geneeskunde, 150(13), 741-746.
Rubella epidemic in the Netherlands in 2004/'05: First newborn with congenital rubella syndrome
A newborn male was diagnosed with congenital rubella syndrome. His 31-year-old mother had had erythematous exanthema during a period of amenorrhea lasting 7 weeks; she was not vaccinated and had never had a rubella infection. The infection was confirmed serologically. The mother gave birth to an icteric, microcephalic, dysmature neonate with hepatosplenomegaly and exanthema with multiple, small purple-red spots. Ultrasound cardiography revealed a persistently open arterial duct and a small defect of the ventricular septum. Radiological evaluation of the long bones showed the characteristic longitudinal lucent strands ('celery stalk appearance'). Ultrasound of the cerebrum showed diffuse widespread calcifications in the white matter and basal ganglia, striatal vasculopathy and diffuse parenchymal disorders. Psychomotor development was impaired. The patient was completely deaf in the left ear and had severely poor hearing in the right ear. After the introduction of the rubella vaccine in the Netherlands in 1974 a substantial decrease was seen in the incidence of rubella infections as well as congenital rubella syndrome. An epidemic of rubella infections has been present within the non-vaccinated population since September 2004. Recognition of the clinical symptoms and confirmation of the clinical suspicion with proper viral diagnostic methods are needed to control the current epidemic and to prevent secundary spread. Infants born with congenital rubella syndrome remain infectious to non-vaccinated individuals for a prolonged period of time; the virus is excreted in the urine and faeces. Long-term medical follow-up is necessary because the congenital rubella infection can cause abnormalities after the neonatal period.
De Mol AC, Vrancken S, Eggink AJ, Verduyn Lunel FM, Warris A (2006). Rubella epidemic in the Netherlands in 2004/'05: First newborn with congenital rubella syndrome [9]. Nederlands Tijdschrift voor Geneeskunde, 150(24).
Warris A, Draaisma JMT (2006). Tuberculosis in the Netherlands. Tijdschrift voor Kindergeneeskunde, 74(1), 21-22.
de Mol AC, Vrancken S, Eggink AJ, Verduyn Lunel FM, Warris A (2006). [The first newborn with congenital rubella syndrome during the rubella epidemic in the Netherlands in 2004/'05]. Ned Tijdschr Geneeskd, 150(13), 741-746.
[The first newborn with congenital rubella syndrome during the rubella epidemic in the Netherlands in 2004/'05].
Mennink-Kersten MASH, Ruegebrink D, Klont RR, Warris A, Gavini F, Op den Camp HJM, Verweij PE (2005). Bifidobacterial lipoglycan as a new cause for false-positive platelia Aspergillus enzyme-linked immunosorbent assay reactivity. J Clin Microbiol, 43(8), 3925-3931.
Bifidobacterial lipoglycan as a new cause for false-positive platelia Aspergillus enzyme-linked immunosorbent assay reactivity.
We previously hypothesized that a lipoglycan of Bifidobacterium bifidum subsp. pennsylvanicum cross-reacts with the Platelia Aspergillus (PA) enzyme-linked immunosorbent assay (ELISA) based on the presence of galactofuranosyl epitopes in the cell wall (M. A. S. H. Mennink-Kersten, R. R. Klont, A. Warris, H. J. M. Op den Camp, and P. E. Verweij, Lancet 363:325-327, 2004). We tested this hypothesis by testing bacterial suspensions of different bifidobacterial species and other gram-positive and -negative bacteria with the PA ELISA, which is used to detect circulating galactomannan for the serodiagnosis of invasive aspergillosis. Furthermore, neonatal fecal samples were enumerated for bifidobacteria by fluorescence in situ hybridization (FISH) and tested for PA ELISA reactivity. All bifidobacteria, except B. infantis and B. adolescentis, showed reactivity 6- to 600-fold higher compared to the controls (i.e. Micrococcus luteus and Propionibacterium freudenreichii, which contain a cell wall lipomannan). Eggerthella lenta showed a 25-fold-higher reactivity. ELISA reactivity was clearly shown to be associated with bacterial lipoglycans containing a beta-1,5-galactofuranosyl chain. All neonatal feces showed PA ELISA reactivity and associated numbers of bifidobacteria. Since high concentrations of bifidobacteria are present in the human gut, these bacteria or excreted lipoglycan may cause false serum PA ELISA reactivity in selected patient groups, especially neonates.
Warris A, Netea MG, Verweij PE, Gaustad P, Kullberg BJ, Weemaes CMR, Abrahamsen TG (2005). Cytokine responses and regulation of interferon-gamma release by human mononuclear cells to Aspergillus fumigatus and other filamentous fungi. MEDICAL MYCOLOGY, 43(7), 613-621. Author URL.
Overland G, Stuestol JF, Dahle MK, Myhre AE, Netea MG, Verweij P, Yndestad A, Aukrust P, Kullberg BJ, Warris A, et al (2005). Cytokine responses to fungal pathogens in Kupffer cells are Toll-like receptor 4 independent and mediated by tyrosine kinases. SCANDINAVIAN JOURNAL OF IMMUNOLOGY, 62(2), 148-154. Author URL.
Bleeker-Rovers CP, Warris A, Drenth JPH, Corstens FHM, Oyen WJG, Kullberg BJ (2005). Diagnosis of Candida lung abscesses by F-18-fluorodeoxyglucose positron emission tomography. CLINICAL MICROBIOLOGY AND INFECTION, 11(6), 493-495. Author URL.
Kroft EBM, Warris A, Jansen LE, van Crevel R (2005). [A Dutchman from Mali with a perianal ulcer caused by cutaneous amoebiasis]. Ned Tijdschr Geneeskd, 149(6), 308-311.
[A Dutchman from Mali with a perianal ulcer caused by cutaneous amoebiasis].
A 66-year-old Dutchman, living in Mali, presented with an extensive progressive perianal ulcer despite local and antibiotic treatment. Microscopic examination of the stool revealed Entamoeba histolytica/dispar cysts and phagocytosing trophozoites were seen in fresh scrapings of the ulcer, a diagnostic feature of infection with E. histolytica. The diagnosis was cutaneous amoebiasis and the patient was effectively treated with metronidazole and local debridements. Primary cutaneous amoebiasis is a rare disease. Diagnosis and treatment are relatively simple but lack of familiarity with the disease may lead to misdiagnosis or diagnosis at a late stage ofthe infection.
Den Hollander JG, De Vries-Sluijs TEMS, Warris A, Schneider AJ, Hartwig NG, Van Der Ende ME (2004). A test forgotten, a sentence for life. Nederlands Tijdschrift voor Obstetrie en Gynaecologie, 117(4), 112-115.
A test forgotten, a sentence for life
Even in the Western world, where anti-retroviral therapy is widely available, babies with AIDS continue to be born. Three mothers are described who were diagnosed as having HIV infection after a diagnosis of HIV/AIDS had been made in recently born infants. Starting in January 2004, the Dutch screening program during pregnancy was extended to include an HIV test for all pregnant women, with an opting-out principle. HIV infection of the infant of an HIV-seropositive mother is preventable and the cases serve to illustrate the importance of testing all pregnant women, whether in a risk group or not.
Mennink-Kersten MASH, Klont RR, Warris A, Op den Camp HJM, Verweij PE (2004). Bifidobacterium lipoteichoic acid and false ELISA reactivity in aspergillus antigen detection. Lancet, 363(9405), 325-327.
Bifidobacterium lipoteichoic acid and false ELISA reactivity in aspergillus antigen detection.
A major difficulty with the detection of circulating galactomannan, a cell-wall polysaccharide released by Aspergillus sp during growth, in the serodiagnosis of invasive aspergillosis is the occurrence of false-positive ELISA results, especially in neonates and infants. On the basis of molecule similarity, we postulate that a lipoteichoic acid of Bifidobacterium sp can act as epitope for the monoclonal antibody used in the ELISA. The neonatal gut is heavily colonised with Bifidobacterium sp and these bacteria or their lipoteichoic acid might cause ELISA reactivity with serum after translocation because of immaturity of the intestinal mucosa. If our hypothesis is correct, we might find a method to discriminate between false-positive and true-positive ELISA results and thereby prevent unnecessary pre-emptive treatment of patients.
Netea MG, Warris A, Van der Meer JWM, Fenton MJ, Verver-Janssen TJG, Jacobs LEH, Andresen T, Verweij PE, Kullberg BJ (2003). Aspergillus fumigatus evades immune recognition during germination through loss of toll-like receptor-4-mediated signal transduction. J Infect Dis, 188(2), 320-326.
Aspergillus fumigatus evades immune recognition during germination through loss of toll-like receptor-4-mediated signal transduction.
Peritoneal macrophages from Toll-like receptor (TLR) 4-deficient ScCr mice produced less tumor necrosis factor, interleukin (IL)-1alpha, and IL-1beta than did macrophages of control mice, when stimulated with conidia, but not with hyphae, of Aspergillus fumigatus, a finding suggesting that TLR4-mediated signals are lost during germination. This hypothesis was confirmed by use of a TLR4-specific fibroblast reporter cell line (3E10) that responded to the conidia, but not to the hyphae, of A. fumigatus. In contrast, macrophages from TLR2-knockout mice had a decreased production of proinflammatory cytokines in response to both Aspergillus conidia and Aspergillus hyphae, and these results were confirmed in 3E10 cells transfected with human TLR2. In addition, Aspergillus hyphae, but not Aspergillus conidia, stimulated production of IL-10 through TLR2-dependent mechanisms. In conclusion, TLR4-mediated proinflammatory signals, but not TLR2-induced anti-inflammatory signals, are lost on Aspergillus germination to hyphae. Therefore, phenotypic switching during germination may be an important escape mechanism of A. fumigatus that results in counteracting the host defense.
Warris A, Netea MG, Wang JE, Gaustad P, Kullberg B-J, Verweij PE, Abrahamsen TG (2003). Cytokine release in healthy donors and patients with chronic granulomatous disease upon stimulation with Aspergillus fumigatus. Scand J Infect Dis, 35(8), 482-487.
Cytokine release in healthy donors and patients with chronic granulomatous disease upon stimulation with Aspergillus fumigatus.
The release of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10 upon stimulation with non-viable conidia and hyphal fragments from Aspergillus fumigatus was investigated in an ex vivo whole-blood model. In healthy volunteers, high numbers of conidia (between 10(6) and 3 x 10(8)/ml) induced a moderate release of TNF-alpha and IL-6. Hyphal fragments (2.5 x 10(5)/ml) were more potent in stimulating the release of these pro-inflammatory cytokines. Although some IL-10 release was observed upon stimulation with either conidia or hyphal fragments, it was not significantly different from that in unstimulated controls. In comparison, in whole blood obtained from 4 patients with chronic granulomatous disease (CGD), a high release of pro-inflammatory cytokines together with a significantly higher IL-10 release than in the healthy controls was seen after stimulation with A. fumigatus. In conclusion, A. fumigatus can trigger the release of pro-inflammatory cytokines in a human whole-blood system, which is likely to be central to the activation of antifungal defence mechanisms. In contrast, A. fumigatus stimulates a higher release of anti-inflammatory cytokines in CGD patients, which may suggest that a dysregulation between pro- and anti-inflammatory cytokines contributes to the increased susceptibility to invasive aspergillosis in this patient group.
Warris A, Klaassen CHW, Meis JFGM, De Ruiter MT, De Valk HA, Abrahamsen TG, Gaustad P, Verweij PE (2003). Molecular epidemiology of Aspergillus fumigatus isolates recovered from water, air, and patients shows two clusters of genetically distinct strains. J Clin Microbiol, 41(9), 4101-4106.
Molecular epidemiology of Aspergillus fumigatus isolates recovered from water, air, and patients shows two clusters of genetically distinct strains.
There has been an increase in data suggesting that besides air, hospital water is a potential source of transmission of filamentous fungi, and in particular Aspergillus fumigatus. Molecular characterization of environmental and clinical A. fumigatus isolates, collected prospectively during an 18-month period, was performed to establish if waterborne fungi play a role in the pathogenesis of invasive aspergillosis. Isolates recovered from water (n = 54) and air (n = 21) at various locations inside and outside the hospital and from 15 patients (n = 21) with proven, probable, or possible invasive aspergillosis were genotyped by amplified fragment length polymorphism analysis. Based on genomic fingerprints, the environmental A. fumigatus isolates could be grouped into two major clusters primarily containing isolates recovered from either air or water. The genotypic relatedness between clinical and environmental isolates suggests that patients with invasive aspergillosis can be infected by strains originating from water or from air. In addition, 12 clusters with genetically indistinguishable or highly related strains were differentiated, each containing two to three isolates. In two clusters, clinical isolates recovered from patients matched those recovered from water sources, while in another cluster the clinical isolate was indistinguishable from one cultured from air. This observation might open new perspectives in the development of infection control measures to prevent invasive aspergillosis in high-risk patients. The genetic variability found between airborne and waterborne A. fumigatus strains might prove to be a powerful tool in understanding the transmission of invasive aspergillosis and in outbreak control.
Berger VW, Franzblau MJ, Verweij PE, Warris A, Weemaes CM, Gallin JI, Wesley R, Holland SM (2003). Preventing fungal infections in chronic granulomatous disease [5] (multiple letters). New England Journal of Medicine, 349(12), 1190-1191.
Verweij PE, Warris A, Weemaes CM (2003). Preventing fungal infections in chronic granulomatous disease. N Engl J Med, 349(12), 1190-1191. Author URL.
Warris A, Voss A, Abrahamsen TG, Verweij PE (2002). Contamination of hospital water with Aspergillus fumigatus and other molds. Clin Infect Dis, 34(8), 1159-1160. Author URL.
Warris A, Weemaes CM, Verweij PE (2002). Multidrug resistance in Aspergillus fumigatus. N Engl J Med, 347(26), 2173-2174. Author URL.
Warris A, Semmekrot BA, Voss A (2001). Candidal and bacterial bloodstream infections in premature neonates: a case-control study. Medical Mycology, 39(1), 75-79.
Candidal and bacterial bloodstream infections in premature neonates: a case-control study
Nosocomial bloodstream infections (BSI) in premature neonates are an important cause of morbidity and mortality. The early and efficient diagnosis of a neonatal BSI and the differentiation between bacterial and fungal BSI remains a challenging task. We compared the clinical features and blood test results in preterm infants with proven candidal or bacterial BSI in order to identify potential risk factors for developing a candidal BSI. Preterm infants with proven candidal BSI were significantly more prematurely born (mean age of gestation 27.7 vs. 29.8 weeks), had previously received significantly more antibiotics of multiple classes (mean 4.4 vs. 1.2) for significantly longer periods (mean 19.3 vs. 3.2 days), were ventilated more intensively, had a significantly longer stay at the neonatal intensive care unit before the onset of the BSI (mean 26.5 vs. 9.4 days), and had C-reactive protein values even higher than in preterm infants with a bacterial BSI (mean 90 vs. 71 mg l-1). The presence of thrombocytopenia (< 150 × 109 cells l-1) in all the preterm infants with candidal BSI was a significant difference. No differences were seen with regard to birth-weight, use of central intravascular catheters, total parenteral nutrition, white blood cell count and differentiation. In conclusion, candidal BSI can be strongly expected after the third week of admittance in the most premature neonates on a respirator and treated with multiple classes of antibiotics for a prolonged period of time. The presence of these risk factors in a 'septic' premature infant on antibiotic treatment justifies the empiric use of antifungals.
Warris A, Semmekrot BA, Voss A (2001). Candidal and bacterial bloodstream infections in premature neonates: a case-control study. Med Mycol, 39(1), 75-79.
Candidal and bacterial bloodstream infections in premature neonates: a case-control study.
Nosocomial bloodstream infections (BSI) in premature neonates are an important cause of morbidity and mortality. The early and efficient diagnosis of a neonatal BSI and the differentiation between bacterial and fungal BSI remains a challenging task. We compared the clinical features and blood test results in preterm infants with proven candidal or bacterial BSI in order to identify potential risk factors for developing a candidal BSI. Preterm infants with proven candidal BSI were significantly more prematurely born (mean age of gestation 27.7 vs. 29.8 weeks), had previously received significantly more antibiotics of multiple classes (mean 4.4 vs. 1.2) for significantly longer periods (mean 19.3 vs. 3.2 days), were ventilated more intensively, had a significantly longer stay at the neonatal intensive care unit before the onset of the BSI (mean 26.5 vs. 9.4 days), and had C-reactive protein values even higher than in preterm infants with a bacterial BSI (mean 90 vs. 71 mg l(-1)). The presence of thrombocytopenia ( < 150 x 10(9) cells l(-1)) in all the preterm infants with candidal BSI was a significant difference. No differences were seen with regard to birth-weight, use of central intravascular catheters, total parenteral nutrition, white blood cell count and differentiation. In conclusion, candidal BSI can be strongly expected after the third week of admittance in the most premature neonates on a respirator and treated with multiple classes of antibiotics for a prolonged period of time. The presence of these risk factors in a 'septic' premature infant on antibiotic treatment justifies the empiric use of antifungals.
Warris A, Voss A, Verweij PE (2001). Hospital sources of Aspergillus: New routes of transmission?. Rev Iberoam Micol, 18(4), 156-162.
Hospital sources of Aspergillus: New routes of transmission?
With the continuing increase in the number of severely immunocompromised patients, hospitals are faced with the growing problem of invasive aspergillosis and other opportunistic fungal infections. Since treatment of these infections are difficult and outcome is often fatal, preventive measures are of major importance in the control of invasive filamentous fungal infections. Until recently, inhalation of airborne conidia was believed to be the primary route of acquiring Aspergillus infection. Despite the fact, that efforts to filter the hospital air has led to a reduction of airborne conidia paralleled by a decrease in the frequency of invasive infections, the correlation between the concentration of Aspergillus conidia in hospital air and the risk of invasive infections remains unclear. Furthermore, alternative modes of transmission may exist and should be recognized and investigated. The discovery of hospital water as a potential source of Aspergillus fumigatus and other filamentous fungi may suggest a new route for the transmission of invasive filamentous fungal infections. Epidemiological studies, based on molecular characterization and comparisons of fungal isolates recovered from patients and environment, are needed to expand our understanding of these alternative routes of transmission.
Warris A, Bjørneklett A, Gaustad P (2001). Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med, 344(14), 1099-1100. Author URL.
Wang JE, Warris A, Ellingsen EA, Jørgensen PF, Flo TH, Espevik T, Solberg R, Verweij PE, Aasen AO (2001). Involvement of CD14 and toll-like receptors in activation of human monocytes by Aspergillus fumigatus hyphae. Infect Immun, 69(4), 2402-2406.
Involvement of CD14 and toll-like receptors in activation of human monocytes by Aspergillus fumigatus hyphae.
Invasive fungal infections represent an increasing problem associated with high mortality. The present study was undertaken to identify leukocyte subsets that are activated by hyphal fragments in a whole-human-blood model, as well as to examine the involvement of CD14 and Toll-like receptors (TLRs) in activation of monocytes by hyphae. Incubation of whole human blood with hyphal fragments from Aspergillus fumigatus and Scedosporium prolificans for 6 h caused induction of mRNAs for tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 in T cells, B cells, and monocytes, but not in granulocytes, as analyzed by reverse transcription-PCR with mRNA isolated from very pure populations of these leukocyte subsets. In primary adherent human monocytes, induction of TNF-alpha by hyphal fragments was dependent on plasma. Heat treatment of plasma at 56 degrees C for 30 min strongly reduced the ability of plasma to prime for activation. Pretreatment of human monocytes with different concentrations (1, 3, and 10 microg/ml) of monoclonal antibody (MAb) HTA125 (anti-TLR4) or MAb 18D11 (anti-CD14) for 30 min inhibited the release of TNF-alpha induced by hyphal fragments in a dose-dependent manner. Maximal inhibitions of 35 and 70% were obtained with 10 microg of HTA125 and 18D11 per ml, respectively. In contrast, pretreatment with MAb TL2.1 (anti-TLR2) did not affect signaling induced by hyphae. Pretreatment with the lipid a antagonist B975 blocked lipopolysaccharide signaling but did not inhibit TNF-alpha production induced by hyphal fragments. Our results suggest that T cells, B cells, and monocytes are involved in the innate immune response to invasive fungal pathogens and that serum components are relevant for activation of monocytes by hyphae. CD14 and TLR4 may be involved in signaling of Aspergillus hyphae in monocytes, but further studies to elucidate this issue are warranted.
Warris A, Gaustad P, Meis JF, Voss A, Verweij PE, Abrahamsen TG (2001). Recovery of filamentous fungi from water in a paediatric bone marrow transplantation unit. J Hosp Infect, 47(2), 143-148.
Recovery of filamentous fungi from water in a paediatric bone marrow transplantation unit.
In order to determine whether water or water-related surfaces are a reservoir for opportunistic filamentous fungi, water sampling in the paediatric bone marrow transplantation (BMT) unit of the National Hospital University of Oslo, Norway was performed. During a six-month period 168 water samples and 20 samples from water-related surfaces were taken. The water samples were taken from the taps and showers in the BMT unit and from the main pipe supplying the paediatric department with water. In addition, 20 water samples were taken at the intake reservoir supplying the city of Oslo with drinking water. Filamentous fungi were recovered from 94% of all the water samples taken inside the hospital with a mean colony forming unit (cfu) count of 2.7/500mL of water. Aspergillus fumigatus was recovered from 49% and 5.6% of water samples from the taps and showers, respectively (mean 1.9 and 1.0cfu/500mL). More than one third (38.8%) of water samples from the main pipe revealed A. fumigatus (mean 2.1cfu/500mL). All water samples taken at the intake reservoir were culture positive for filamentous fungi, 85% of the water samples showed A. fumigatus (mean 3.1cfu/500mL). Twenty-five percent of water-related surfaces yielded filamentous fungi, but A. fumigatus was recovered from only two samples. We showed that filamentous fungi are present in the hospital water and to a lesser extent on water-related surfaces. The recovery of filamentous fungi in water samples taken at the intake reservoir suggests that the source of contamination is located outside the hospital.
Warris A, Wesenberg F, Gaustad P, Verweij PE, Abrahamsen TG (2000). Acremonium strictum fungaemia in a paediatric patient with acute leukaemia. SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES, 32(4), 442-444. Author URL.
Warris A, Verweij PE, Barton R, Crabbe DC, Evans EG, Meis JF (1999). Invasive aspergillosis in two patients with Pearson syndrome. Pediatr Infect Dis J, 18(8), 739-741. Author URL.
Henriet S, Verweij PE, Holland SM, Warris A (2013). Invasive Fungal Infections in Patients with Chronic Granulomatous Disease. In (Ed) HOT TOPICS IN INFECTION AND IMMUNITY IN CHILDREN IX, 27-55. Author URL.
Warris A, Kroon FP (2010). Viral exanthems. In (Ed) Infectious Diseases: Third Edition, 99-108.
Mahdi KA (2001). Introduction. In Mahdi KA (Ed) Water in the Arabian Peninsula: Problems and Policies, Ithaca Press, 1-15.
Warris A (2018). Defective antifungal immunity in cystic fibrosis. Author URL.
Turner S, Warris A, an S-Q (2018). Microbiome Characteristics of Induced Sputum compared to Bronchial Fluid and Upper Airway Samples. Author URL.
Bastiaans D, Immohr I, Zeinstra G, Bartels-Wilmer C, Smeets O, Von der Flier M, Strik-Albers R, Pein M, Colbers A, Burger D, et al (2018). The VALID-project: Development of a new paediatric formulation of valaciclovir. Author URL.
Ballard E, Weber J, Brakhage AA, Zoll J, Melchers WJG, Brown AJP, Verweij PE, Warris A (2018). Using CRISPR/Cas9 to unravel the complex role of single nucleotide substitutions in Aspergillus fumigatus in-host adaptation. Author URL.
Lehrnbecher T, Warris A (2017). Antifungal prophylaxis in immunocompromised children. Author URL.
Bercusson A, De Boer L, Warris A, Armstrong-James D (2017). CFTR REGULATES NORMAL MACROPHAGE RESPONSES TO ASPERGILLUS FUMIGATUS. Author URL.
Westra D, Kurvers RAJ, van den Heuvel LP, Wurzner R, van de Karl NCA, Warris A (2013). Compound heterozygous mutations in the C6-gene in a child with relapsing bacterial and viral infections. Author URL.
van Jaarsveld P, Gordijn S, Gemke RJB, Kaspers GJL, de Goffau A, van Esch J, de Vries E, Warris A, Driessen GJ (2012). FATIGUE IN CHILDREN WITH PRIMARY ANTIBODY DEFICIENCY. Author URL.
IJspeert H, Warris A, van Flier M, Chishimba S, van Dongen JJM, van Gent DC, van der Burg M (2012). LIGASE-4 DEFICIENT PATIENT WITH a NEW VERY SEVERE PHENOTYPE DUE TO C-TERMINALLY TRUNCATING MUTATIONS. Author URL.
Driessen GJ, IJspeert H, Weemaes C, Harraldsson A, Trip M, Warris A, van der Flier M, Wulffraat N, Verhagen MMM, Taylor MM, et al (2012). SEVERITY OF ANTIBODY DEFICIENCY IN ATAXIA TELANGIECTASIA IS ASSOCIATED WITH INTRINSIC DEFECTS IN B- AND T-CELL DEVELOPMENT. Author URL.
de Boer M, van Leeuwen K, Kuijpers TW, Weemaes CM, Warris A, van den Berg TK, Vinckenbosch N, Roos D (2011). Chronic granulomatous disease caused by a partly exonised retroposed TMF1 gene copy inserted into the CYBB gene. Author URL.
Warris A (2011). The environment and human mycoses: water. Author URL.
Warris A (2010). FUNGAL INFECTIONS - PREVENTION AND TREATMENT. Author URL.
Henriet SSV, Rijs AJMM, Verweij PE, Hermans PWM, Warris A (2009). Distinctive ROS function induced by Aspergillus nidulans and Aspergillus fumigatus during in vitro phagocytosis by X-CGD monocytes. Author URL.
Kelly A, Weiss M (2009). Preface.
Warris A (2009). Primary immunodeficiencies and fungal infections. Author URL.
Van der Linden JWM, Bruggemann RJM, Knoop J, Verweij PE, Burger DM, Warris A (2009). Therapeutic drug monitoring of voriconazole in pediatric patients. Author URL.
Chai L, Netea M, Vonk A, Warris A, Kutberg BJ (2008). Aspergillus attenuates distinct host TLR2 & TLR4 responses. Author URL.
Noordzij JG, Seyger M, Preijers F, Hoogerbrugge P, de Groot R, van de Vosse E, Lankester AC, van der Burg M, Warris A (2008). Early diagnosis of hypohidrotic ectodermal dysplasia with immune deficiency due to NEMO mutation successfully cured by BMT. Author URL.
IJspeert H, Lankester AC, Weemaes CMR, Warris A, Wiegant W, Van Zelm MC, van Tol MJD, van Gent DC, van Dongen JJM, van der Burg M, et al (2008). New type of SCID due to aberrant Artemis splicing. Author URL.
Klont RR, Noordzij JG, Bot P, Schulin-Casonato T, Warris A (2007). A child with endocarditis due to Enterobacter cloacae responded to long-term antibiotic treatment without cardiac surgery. Author URL.
van de Wetering M, Goossen G, Warris A (2007). Influenza vaccination in children with cancer, a Cochrane systematic review. Author URL.
Klont RR, Rijs AJM, Warris A, Sturm PDJ, Melchers WJG, Verweij PE (2006). Legionella pneumophila in commercial bottled mineral water. Author URL.
Kroft EBM, Warris A, Jansen LE, Van Crevel R, De Hoop D (2005). A Dutchman from Mali with a perianal ulcer caused by cutaneous amoebiasis.
A Dutchman from Mali with a perianal ulcer caused by cutaneous amoebiasis
Warris A, Verweij PE (2005). Clinical implications of environmental sources for Aspergillus. Author URL.
Overland G, Stuestol JF, Dahle MK, Myhre A, Netea MG, Warris A, Verweij PE, Kullberg BJ, Wang JE, Aasen AO, et al (2005). Innate responses of Kupffer cells to fungal pathogens seems to involve Src tyrosin kinase, but does not involve TLR4. Author URL.
Wang JE, Warris A, Elllingsen EA, Jorgensen PF, Flo TH, Espevik T, Solberg R, Verweij PE, Aasen AO (2001). Involvement of CD14 and toll-like receptors in signalling by Aspergillus hyphae. Author URL.
Gil-Lamaignere C, Warris A, Abrahamsen T, Roilides E (2000). Inhibition of neutrophil oxidative burst by Scedosporium prolificans and Aspergillus fumigatus hyphae. Author URL.
Warris A, Semmekrot B, Voss A (1998). Case-control study of candidemia vs. bacteremia in a neonatal intensive care unit. Author URL.
Adilia_Warris Details from cache as at 2023-01-29 15:27:27
BIOM702Z - Fungal Diseases