Etiology and risk factors of febrile neutropenia in children during cancer treatment

Side effects due to chemotherapy is still a major issue during cancer treatment. Febrile neutropenia and associated microbiological defined infections (MDIs) are dreaded complications, and still a cause of death during pediatric cancer treatment. In many of the febrile neutropenia episodes the cause of the fever is unknown, and risk factors of developing febrile neutropenia are poorly characterized. To be able to pin-point children at risk of febrile neutropenia and anticipate those at risk of more severe episodes could lead to more individualized treatment. Therefore, the aim of this thesis was two-fold: to investigate the microbiological causes of febrile neutropenia episodes and to investigate risk factors of developing this condition and associated MDIs. In papers I and IV, causes of febrile neutropenia episodes were assessed. In paper I, we identified a respiratory virus in 45% of the episodes, which was in line with earlier reports. In addition, followup nasopharyngeal sampling showed that only rhinovirus and coronavirus were persistent and all other viruses cleared from the nasal cavity. This indicated that the respiratory virus identified was indeed the cause of the fever. However, causality could not be established. Therefore, paper IV investigated the innate immune response during these episodes. By using gene-expression profiling, the aim was to investigate specific innate signatures in blood. Unfortunately, due to the immunosuppression, there was insufficient RNA from ~30% of the samples and a specific innate signature, similar to that of immunocompetent children, could not be identified. Therefore, the feasibility of using geneexpression profiling to correlate the microbiological findings to an active infection and as a diagnostic tool in children treated for cancer remains challenging. In papers II and III, risk factors of developing neutropenia and febrile neutropenia with associated MDI and low end doses of 6-Mercaptopurine (6-MP) during pediatric ALL treatment were addressed. In paper II, genetic variants in important enzymes involved in drug metabolism were investigated. Here, TPMT genetic variants were associated with a decreased risk of developing neutropenia and febrile neutropenia during the maintenance II period, and deficiency in ITPA (rs1127345) to a decreased risk of developing febrile neutropenia (unadjusted). In addition, genetic variants in NUDT15 were associated with decreased end doses of 6-MP. From the results from paper II, we could still not fully understand the role of TPMT and ITPA and the risk of febrile neutropenia. In addition, NUDT15 seem to play an important role for the 6-MP doses. However, due to the small samples sizes, our results need further investigation in larger cohorts. In paper III, the febrile neutropenia episodes were characterized and genetic variants in important innate immune proteins were investigated. Viral infections were the most common detected infection during febrile neutropenia episodes. However, in the majority of the episodes the cause of the fever remained unknown. TLR4 genetic variants increased the risk of viral infections and variants in the IL-1Ra gene decreased the risk of developing bacterial bloodstream infection. There were no association between MBL and the investigated genetic variants. Therefore, TLR4 and IL-1Ra seem to have a role during infectious episodes in children treated for cancer, however, the results needs to be confirmed in future studies. In conclusion, respiratory virus are common during febrile neutropenia. However, additional more sensitive methods are needed to be able to identify and prove causality between the microbiological findings and the febrile neutropenia episode. Some of the investigated genetic variants seem to play a role in the risk of developing febrile neutropenia and infections. However, some of these need to be further evaluated before any modifications of the management of febrile neutropenia could be recommended

Interactions between seasonal human coronaviruses and implications for the SARS-CoV-2 pandemic: A retrospective study in Stockholm, Sweden, 2009-2020

The four seasonal coronaviruses 229E, NL63, OC43, and HKU1 are frequent causes of respiratory infections and show annual and seasonal variation. Increased understanding about these patterns could be informative about the epidemiology of SARS-CoV-2.; Results from PCR diagnostics for the seasonal coronaviruses, and other respiratory viruses, were obtained for 55,190 clinical samples analyzed at the Karolinska University Hospital, Stockholm, Sweden, between 14 September 2009 and 2 April 2020.; Seasonal coronaviruses were detected in 2130 samples (3.9 %) and constituted 8.1 % of all virus detections. OC43 was most commonly detected (28.4 % of detections), followed by NL63 (24.0 %), HKU1 (17.6 %), and 229E (15.3 %). The overall fraction of positive samples was similar between seasons, but at species level there were distinct biennial alternating peak seasons for the Alphacoronaviruses, 229E and NL63, and the Betacoronaviruses, OC43 and HKU1, respectively. The Betacoronaviruses peaked earlier in the winter season (Dec-Jan) than the Alphacoronaviruses (Feb-Mar). Coronaviruses were detected across all ages, but diagnostics were more frequently requested for paediatric patients than adults and the elderly. OC43 and 229E incidence was relatively constant across age strata, while that of NL63 and HKU1 decreased with age.; Both the Alphacoronaviruses and Betacoronaviruses showed alternating biennial winter incidence peaks, which suggests some type of immune mediated interaction. Symptomatic reinfections in adults and the elderly appear relatively common. Both findings may be of relevance for the epidemiology of SARS-CoV-2

Efficacy and cost-effectiveness of therapist-guided internet cognitive behavioural therapy for paediatric anxiety disorders : a single-centre, single-blind, randomised controlled trial

Background: Paediatric anxiety disorders are prevalent and associated with substantial disability and long-term adverse consequences. Only a minority of affected children have access to evidence-based treatment; internet-delivered cognitive behaviour therapy (ICBT) could help increase accessibility but needs further rigorous evaluation. The objective of this trial was to evaluate the clinical efficacy and cost-effectiveness of ICBT in the treatment of paediatric anxiety disorders. Methods: In this single-blind randomised controlled trial, children 8-12 years with a principal anxiety disorder diagnosis were randomly allocated (1:1) to ICBT or internet-delivered child-directed play (ICDP), an active comparator aimed to improve parent-child relationships and increase child self-esteem without directly targeting anxiety. The study was conducted at a single site within the Stockholm specialist child and adolescent mental health services (CAMHS). Primary endpoint was clinician-rated symptom severity (CSR) of the principal anxiety disorder at post-treatment. All participants were included in the primary analysis (intent-to-treat). Trial registration number: NCT02350257. Findings: Participants (N=131) were recruited between March 2015 and October 2016, mainly via advertisement and referrals from CAMHS, and allocated to ICBT (n=66) or ICDP (n=65). Analyses revealed greater reduction of symptom severity in favour of ICBT (mean difference 0·79, 95% CI 0·42 to 1·16, p=0·002; Cohen’s d=0·77, 95% CI 0·40 to 1·15) and at post-treatment, 48% (n=29) of participants randomised to ICBT no longer fulfilled their principal diagnosis, compared to 15% (n=9) in ICDP (odds ratio 5·41, 95% CI 2·26 to 12·90, p<0·0001). Numbers needed to treat were 3 (95% CI 2·85 to 3·15). Treatment gains were maintained at 3-month follow-up, at which point 70% (n=40) of participants randomised to ICBT no longer met the criteria for their principal anxiety disorder. ICBT resulted in an average societal cost saving of €493·05 (95% CI 477·17 to 508·92) per participant. No severe adverse events were reported. Interpretation: ICBT is a cost-effective treatment for paediatric anxiety disorders that should be considered for implementation in routine clinical care.The Swedish Research Council for Health, Working Life and WelfareStockholm County CouncilAccepte

The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease

Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T1/T2/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (Pcorrected < 0.05). We further examined the association of structural brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were more prominent in patients with myotonic dystrophy type 1 with less white matter affection (early disease stages), contrary to patients with myotonic dystrophy type 2. Thus, depression in myotonic dystrophies might be a reactive adjustment disorder rather than a direct consequence of structural brain damage. Associations of white matter affection with age/disease duration as well as patterns of cerebral water diffusion parameters pointed towards an ongoing process of myelin destruction and/or axonal loss in our cross-sectional study design. Our data suggest that both myotonic dystrophy types 1 and 2 are serious white matter diseases with prominent callosal body and limbic system affection. White matter changes dominated the extent of grey matter changes, which might argue against Wallerian degeneration as the major cause of white matter affection in myotonic dystrophies

Increase in stress contributes to impaired jaw function in juvenile idiopathic arthritis : a two-year prospective study

BackgroundStress in patients with Juvenile Idiopathic Arthritis (JIA) has been found to be associated with orofacial pain, psychological distress, jaw dysfunction and loss of daily activities in a cross-sectional study. The aim of this study was to investigate the relations between stress and change of stress over time versus changes in orofacial pain, psychosocial factors and jaw function over a two-year period in patients with JIA.MethodsThis is a two-year prospective follow-up study involving 40 JIA patients. At baseline (2015) the median age was 12 years and at two-year follow up (2018) 14 years. The JIA patients were examined clinically and with questionnaires at baseline and follow-up with the diagnostic criteria for temporomandibular disorders (DC/TMD) and completed the same set of DC/TMD questionnaires regarding orofacial pain symptoms and psychosocial factors.ResultsChange in stress was associated with change in catastrophizing, psychological distress as well as limitation in general function and jaw function.ConclusionsThis study emphasizes the importance of maintaining a low stress level in patients with JIA since an increase in stress level over a two-year period seems to impair jaw function as well as psychological distress and catastrophizing

Genetic Sequence Variants in TLR4, MBL or IL-1 Receptor Antagonist is not Associated to Increased Risk for Febrile Neutropenia in Children with ALL

Sequence variants in genes involved in the immune system have previously been linked to neutropenia as well as infections in cancer patients. Sequence variants in genes coding for TLR4, MBL, and IL-1Ra were investigated in relation to clinical utility of identifying severe episodes of febrile neutropenia (FN) in a cohort of children undergoing treatment for acute lymphoblastic leukemia. The study included 122 children, where data on FN and microbiological findings were retrospectively collected from medical records. Sequence variants in genes coding for MBL, TLR4, and IL-1Ra were identified by pyrosequencing, TaqMan SNP genotyping assay, and gel electrophoresis. A total of 380 episodes of FN were identified and in 139 episodes, there was a microbiological defined infection. Age and treatment intensity were all associated with the risk of developing FN. No sequence variant was associated to increased numbers of FN episodes. Two sequence variants in the TLR4 gene increased the risk of viral infection, whilst sequence variants in the IL-1Ra gene were associated to a decreased risk of bacterial blood-stream infection (BSI). The investigated sequence variants did not associate with increased risk for FN or to severe infections, as to why the clinical utility as a risk-stratification tool is low. Most episodes of FN were classified as fever with unknown origin, emphasizing the need for improved microbial detection methods.Funding Agencies|Swedish Childhood Cancer Foundation; Swedish Society of Medicine</p

The Feasibility of Host Transcriptome Profiling as a Diagnostic Tool for Microbial Etiology in Childhood Cancer Patients with Febrile Neutropenia

Infection is a common and serious complication of cancer treatment in children that often presents as febrile neutropenia (FN). Gene-expression profiling techniques can reveal transcriptional signatures that discriminate between viral, bacterial and asymptomatic infections in otherwise healthy children. Here, we examined whether gene-expression profiling was feasible in children with FN who were undergoing cancer treatment. The blood transcriptome of the children (n = 63) was investigated at time of FN diagnosed as viral, bacterial, co-infection or unknown etiology, respectively, and compared to control samples derived from 12 of the patients following the FN episode. RNA sequencing was successful in 43 (68%) of the FN episodes. Only two genes were significantly differentially expressed in the bacterial versus the control group. Significantly up-regulated genes in patients with the other three etiologies versus the control group were enriched with cellular processes related to proliferation and cellular stress response, with no clear enrichment with innate responses to pathogens. Among the significantly down-regulated genes, a few clustered into pathways connected to responses to infection. In the present study of children during cancer treatment, the blood transcriptome was not suitable for determining the etiology of FN because of too few circulating immune cells for reliable gene expression analysis

The Applicability of a 2-Transcript Signature to Identify Bacterial Infections in Children with Febrile Neutropenia

Febrile neutropenia is a common complication during chemotherapy in paediatric cancer care. In this setting, clinical features and current diagnostic tests do not reliably distinguish between bacterial and viral infections. Children with cancer (n = 63) presenting with fever and neutropenia were recruited for extensive microbiological and blood RNA sampling. RNA sequencing was successful in 43 cases of febrile neutropenia. These were classified as having probable bacterial infection (n = 17), probable viral infection (n = 13) and fever of unknown origin (n = 13) based on microbiological defined infections and CRP cut-off levels. RNA expression data with focus on the 2-transcript signature (FAM89A and IFI44L), earlier shown to identify bacterial infections with high specificity and sensitivity, was implemented as a disease risk score. The median disease risk score was higher in the probable bacterial infection group, −0.695 (max 2.795; min −5.478) compared to the probable viral infection group −3.327 (max 0.218; min −7.861), which in ROC analysis corresponded to a sensitivity of 0.88 and specificity of 0.54 with an AUC of 0.80. To further characterise the immune signature, analysis of significantly expressed genes and pathways was performed and upregulation of genes associated to antibacterial responses was present in the group classified as probable bacterial infection. Our results suggest that the 2-transcript signature may have a potential use as a diagnostic tool to identify bacterial infections in immunosuppressed children with febrile neutropenia

The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey

We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P &lt; .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature

Prenatal Gyrification Pattern Affects Age at Onset in Frontotemporal Dementia

The paracingulate sulcus is a tertiary sulcus formed during the third trimester. In healthy individuals paracingulate sulcation is more prevalent in the left hemisphere. The anterior cingulate and paracingulate gyri are focal points of neurodegeneration in behavioral variant frontotemporal dementia (bvFTD). This study aims to determine the prevalence and impact of paracingulate sulcation in bvFTD. Structural magnetic resonance images of individuals with bvFTD (n = 105, mean age 66.9 years), Alzheimer's disease (n = 92, 73.3), and healthy controls (n = 110, 62.4) were evaluated using standard protocol for hemispheric paracingulate sulcal presence. No difference in left hemisphere paracingulate sulcal frequency was observed between groups; 0.72, 0.79, and 0.70, respectively, in the bvFTD, Alzheimer's disease, and healthy control groups, (P = 0.3). A significant impact of right (but not left) hemispheric paracingulate sulcation on age at disease onset was identified in bvFTD (mean 60.4 years where absent vs. 63.8 where present [P = 0.04, Cohen's d = 0.42]). This relationship was not observed in Alzheimer's disease. These findings demonstrate a relationship between prenatal neuronal development and the expression of a neurodegenerative disease providing a gross morphological example of brain reserve