Publications by authors named "Marie Helleberg"

78 Publications

Improved survival among hospitalized patients with COVID-19 treated with remdesivir and dexamethasone. A nationwide population-based cohort study.

Clin Infect Dis 2021 Jun 10. Epub 2021 Jun 10.

Department of Medicine, Zealand University Hospital, Roskilde, Denmark.

Background: There is limited data on outcomes of moderate to severe Coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting.

Objective: To compare the effectiveness of standard of care (SOC) alone vs SOC plus remdesivir and dexamethasone.

Methods: Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI).

Results: The 30-d mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI, 0.38-0.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36 (95% CI, 0.29-0.46)).

Conclusions And Relevance: Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May.
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http://dx.doi.org/10.1093/cid/ciab536DOI Listing
June 2021

COVID-19 vs influenza A/B supeRInfectionS in the IntenSive care unit (CRISIS): Protocol for a Danish nationwide cohort study.

Acta Anaesthesiol Scand 2021 Jun 4. Epub 2021 Jun 4.

Dept. Of Intensive Care, 4131, Rigshospitalet, University of Copenhagen, Capital Region of Denmark, Blegdamsvej 9, 2100, Copenhagen Ø.

Background: Superinfection following viral infection is a known complication, which may lead to longer hospitalisation and worse outcome. Empirical antibiotic therapy may prevent bacterial superinfections, but may also lead to overuse, adverse effects and development of resistant pathogens. Knowledge about the incidence of superinfections in intensive care unit (ICU) patients with severe Coronavirus Disease 2019 (COVID-19) is limited.

Methods: We will conduct a nationwide cohort study comparing the incidence of superinfections in patients with severe COVID-19 admitted to the ICU compared with ICU patients with influenza A/B in Denmark. We will include approximately 1000 patients in each group from the time period of October 1 , 2014 to April 30 , 2019 and from March 10 , 2020 to March 1 , 2021 for patients with influenza and COVID-19, respectively. The primary outcome is any superinfection within 90 days of admission to the ICU. We will use logistic regression analysis comparing COVID-19 with influenza A/B after adjustment for relevant predefined confounders. Secondarily, we will use unadjusted and adjusted logistic regression analyses to assess six potential risk factors (sex, age, cancer (including haematological), immunosuppression, use of life support on day 1 in the ICU) for superinfections, and compare outcomes in patients with COVID-19 with/without superinfections, and present descriptive data regarding the superinfections.

Conclusion: This study will provide important knowledge about superinfections in ICU patients with severe COVID-19.
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http://dx.doi.org/10.1111/aas.13934DOI Listing
June 2021

Postpartum disseminated HSV-1 infection with hemophagocytic lymphohistiocytosis and fulminant neonatal herpes infection.

J Infect Dis 2021 May 26. Epub 2021 May 26.

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.

The present study describes a 19-year-old woman with systemic herpes simplex virus (HSV)-1 infection postpartum, and a fatal course of neonatal herpesvirus infection. The mother experienced an unusual disease course with hemophagocytic lymphohistiocytosis (HLH) and persistence of HSV-1 DNA for 15 weeks. Functional investigation of cells from the mother demonstrated significantly impaired induction of antiviral interferons and cytokines in response to viruses and various ligands in the context of normal activation of the transcription factors NF-κB and IRF3. Whole exome sequencing did not reveal any functionally validated genetic variants. We suggest that the functionally impaired antiviral responses, potentially caused by a mutation in CASP8 or other variants in non-coding regions of the genome, contributed to the unusually severe disease course in two generations with disseminated HSV-1 infection evolving into HLH in the mother, and a fatal neonatal HSV-1 infection.
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http://dx.doi.org/10.1093/infdis/jiab290DOI Listing
May 2021

Genetic variants and immune responses in a cohort of patients with varicella zoster virus encephalitis.

J Infect Dis 2021 May 11. Epub 2021 May 11.

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.

Background: Infection with varicella zoster virus (VZV) may involve different central nervous system (CNS) manifestations, including meningitis, encephalitis, and vasculitis. In cases where otherwise healthy individuals are affected, an inborn error of immunity may underlie increased susceptibility or severity of infection.

Methods: We collected a cohort of 17 adults who experienced VZV encephalitis and performed whole exome sequencing. Patient PBMCs were infected with VZV and innate antiviral interferon and cytokine responses as well as viral replication was evaluated. Data were analyzed by Mann Whitney U test.

Results: We identified a total of 21 different potentially disease-causing variants in a total of 13 of the 17 patients included. These gene variants were within two major functional clusters: i) innate viral sensors and immune pathways and ii) autophagy pathways. Antiviral interferon (IFN) and cytokine responses were abnormal in the majority of patients, whereas viral replication was increased in only 2/17.

Conclusion: This study identifies a list of variants of pathogenic potential, which may serve as a platform for generating hypotheses for future studies addressing genetic and immunological factors associated with susceptibility to VZV encephalitis. Collectively, these data suggest that disturbances in innate sensing and autophagy pathways may predispose to VZV encephalitis.
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http://dx.doi.org/10.1093/infdis/jiab254DOI Listing
May 2021

Therapeutic Drug Monitoring of Isavuconazole: Serum Concentration Variability and Success Rates for Reaching Target in Comparison with Voriconazole.

Antibiotics (Basel) 2021 Apr 23;10(5). Epub 2021 Apr 23.

Unit of Mycology, Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark.

Isavuconazole (ISZ) is used in the treatment of aspergillosis and mucormycosis. The purpose of this study was to evaluate the therapeutic drug monitoring (TDM) of ISZ samples from a clinical setting performed at Statens Serum Institut. Isavuconazole serum concentrations were determined by fluorescent detection on a UHPLC. Serum-ISZ (s-ISZ) results were included and compared to those of serum-voriconazole (s-VRZ) in a 33 month period from March 2017. Clinical data were obtained for patients receiving ISZ. The therapeutic range was initially 2-10 mg/L, but was adjusted to 2-5 mg/L during the study period except for selected patients with Mucorales infections who received off-label doses of ISZ. A total of 273 s-ISZ and 1242 s-VRZ measurements from 35 and 283 patients, respectively, were included. Seventeen patients had received both ISZ and VRZ with TDM within the study period. The median s-ISZ was 4.3 mg/L (0.5-15.4 mg/L) with 83% of measurements within the therapeutic index. The median s-VRZ was 2.6 mg/L (0.2-21.9 mg/L) with 67% of measurements within the therapeutic index. The median intra-/interindividual coefficient of variation (CV) was 43.4%/54.8% for ISZ compared to 53.2%/83.3% for VRZ. For patients receiving ISZ, the adverse events were mostly gastroenteric and few drug-drug interactions were observed. Furthermore, immediate change from ISZ to VRZ treatment seemed to lead to prolonged metabolism of ISZ with detection up to 35 days after discontinuation. The majority of patients achieved s-ISZ levels well within the therapeutic range with less intra/interindividual CV than patients receiving VRZ.
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http://dx.doi.org/10.3390/antibiotics10050487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145181PMC
April 2021

Dissection of the Activity of Agricultural Fungicides against Clinical Isolates with and without Environmentally and Medically Induced Azole Resistance.

J Fungi (Basel) 2021 Mar 11;7(3). Epub 2021 Mar 11.

Unit for Mycology, Statens Serum Institut, 2300 Copenhagen, Denmark.

Azole resistance is an emerging problem in patients with aspergillosis. The role of fungicides for resistance development and occurrence is not fully elucidated. EUCAST reference MICs of 17 fungicides (11 azoles and 6 others), five azole fungicide metabolites and four medical triazoles were examined against two reference and 28 clinical isolates of , and with ( = 12) and without ( = 16) resistance mutations. Eight/11 azole fungicides were active against wild-type , and , including four (metconazole, prothioconazole-desthio, prochloraz and imazalil) with low MIC (≤2 mg/L) against all three species and epoxiconazole, propiconazole, tebuconazole and difenoconazole also against wild-type . Mefentrifluconazole, azole metabolites and non-azole fungicides MICs were >16 mg/L against although partial growth inhibition was found with mefentrifluconazole. Moreover, mefentrifluconazole and axozystrobin were active against wild-type . Increased MICs (≥3 dilutions) were found for TR/L98H, TR/L98H, TR/Y121F/T289A and G432S compared to wild-type for epoxiconazole, propiconazole, tebuconazole, difenoconazole, prochloraz, imazalil and metconazole (except G432S), and for prothioconazole-desthio against TR/Y121F/T289A, specifically. Increased MICs were found in harbouring G54R, M220K and M220R alterations for five, one and one azole fungicides, respectively, compared to MICs against wild-type . Similarly, increased MICs wer found for with G51A, M217I and Y491H alterations for five, six and two azole fungicides, respectively. Azole fungicides showed activity against wild-type , and , but not against all mutant isolates, suggesting the environmental route of azole resistance may have a role for all three species.
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http://dx.doi.org/10.3390/jof7030205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001900PMC
March 2021

[Diagnostic approach and evaluation of hospitalized patients with COVID-19].

Ugeskr Laeger 2021 03;183(9)

COVID-19 is the infectious disease caused by coronavirus SARS-CoV-2. The most common symptoms of COVID-19 are dry cough, tiredness and fever. Most patients recover from COVID-19 within a few weeks, but some patients have symptoms lasting for weeks or even months after recovery from acute illness, such as fatigue, shortness of breath and cough. This is a review of what we currently know about the clinical disease and its severity as well as which diagnostic strategies are recommended during and after hospital admission.
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March 2021

[Clinical management of hospitalised patients with COVID-19].

Ugeskr Laeger 2021 03;183(9)

COVID-19 is the infectious disease caused by SARS-CoV-2. This is a review of the current treatment strategies available for patients with COVID-19 during hospital admission. Patients requiring hospitalisation frequently suffer from respiratory failure and may require oxygen therapy. Insufficient response to oxygen may be an indication, that other modalities such as high-flow nasal cannula, continuous positive airway pressure or mechanical ventilation are needed. The only medical treatments currently being used are remdesivir and dexamethasone.
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March 2021

Hematological toxicity in patients with solid malignant tumors treated with radiation - Temporal analysis, dose response and impact on survival.

Radiother Oncol 2021 05 1;158:175-183. Epub 2021 Mar 1.

Centre of Excellence for Health, Immunity and Infections (CHIP), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Purpose: To describe the kinetics of the peripheral blood components after radiotherapy, to examine radiation exposure vs. End-of-Radiation-Therapy (EoRT) counts and to associate the EoRT lymphocyte count with death and cancer treatment failure.

Materials And Methods: Cohort study of patients who received curative intent radiotherapy for solid tumor diagnoses from 2009-2016 at Rigshospitalet, Copenhagen and had available 3D radiation exposure data. We illustrated peripheral blood count kinetics within 12 months before and after radiotherapy start and analyzed the impact of the irradiated body volume. We investigated overall survival and cancer treatment failure according to EoRT lymphopenia using Cox regression analyses.

Results: We analyzed 4055 patients with both pre-treatment and EoRT platelet counts and 2318 patients who also had neutrophil and lymphocyte counts. Only the lymphocyte decline after radiotherapy start was clinically relevant and remained low one year after radiotherapy. The higher the volume of the body exposed to radiation, the lower the EoRT blood counts. Female gender (p < 0.001), number of fractions (p = 0.010), dose-volume (p < 0.001) and concomitant use of chemotherapy, particularly the platinum compounds (p < 0.001) were independently associated with a lower EoRT lymphocyte count. Patients with head and neck cancer had the lowest EoRT lymphocyte count. Patients with lymphopenia had a higher risk of death in the year after radiotherapy, compared with patients with no lymphopenia.

Conclusion: Radiation schemes with fewer fractions and radiation techniques allowing reduction of the volume of the body exposed to radiation could be expected to better preserve patients' immune function.
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http://dx.doi.org/10.1016/j.radonc.2021.02.029DOI Listing
May 2021

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

Acta Anaesthesiol Scand 2021 Jul 9;65(6):834-845. Epub 2021 Mar 9.

Department of Anaesthesia and Critical Care Medicine, Odense University Hospital, Odense C, Denmark.

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear.

Methods: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol.

Discussion: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.
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http://dx.doi.org/10.1111/aas.13795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014264PMC
July 2021

Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis.

Acta Anaesthesiol Scand 2021 05 25;65(5):702-710. Epub 2021 Feb 25.

Department of Anaesthesia and Critical Care Medicine, Odense University Hospital, Odense C, Denmark.

Background: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia.

Methods: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors.

Discussion: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results.

Trial Registration: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.
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http://dx.doi.org/10.1111/aas.13793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014670PMC
May 2021

Developing and validating COVID-19 adverse outcome risk prediction models from a bi-national European cohort of 5594 patients.

Sci Rep 2021 02 5;11(1):3246. Epub 2021 Feb 5.

Clinical Pharmacology Unit, Zealand University Hospital, Roskilde, Denmark.

Patients with severe COVID-19 have overwhelmed healthcare systems worldwide. We hypothesized that machine learning (ML) models could be used to predict risks at different stages of management and thereby provide insights into drivers and prognostic markers of disease progression and death. From a cohort of approx. 2.6 million citizens in Denmark, SARS-CoV-2 PCR tests were performed on subjects suspected for COVID-19 disease; 3944 cases had at least one positive test and were subjected to further analysis. SARS-CoV-2 positive cases from the United Kingdom Biobank was used for external validation. The ML models predicted the risk of death (Receiver Operation Characteristics-Area Under the Curve, ROC-AUC) of 0.906 at diagnosis, 0.818, at hospital admission and 0.721 at Intensive Care Unit (ICU) admission. Similar metrics were achieved for predicted risks of hospital and ICU admission and use of mechanical ventilation. Common risk factors, included age, body mass index and hypertension, although the top risk features shifted towards markers of shock and organ dysfunction in ICU patients. The external validation indicated fair predictive performance for mortality prediction, but suboptimal performance for predicting ICU admission. ML may be used to identify drivers of progression to more severe disease and for prognostication patients in patients with COVID-19. We provide access to an online risk calculator based on these findings.
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http://dx.doi.org/10.1038/s41598-021-81844-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864944PMC
February 2021

Defects in and underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans.

Sci Immunol 2020 12;5(54)

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.

Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including and , led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.
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http://dx.doi.org/10.1126/sciimmunol.abc2691DOI Listing
December 2020

Associations of the gut microbiome and clinical factors with acute GVHD in allogeneic HSCT recipients.

Blood Adv 2020 11;4(22):5797-5809

Department of Hematology, Rigshospitalet, Copenhagen, Denmark.

Acute graft-versus-host disease (aGVHD) is a leading cause of transplantation-related mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). 16S ribosomal RNA (16S rRNA) gene-based studies have reported that lower gut bacterial diversity and the relative abundance of certain bacteria after aHSCT are associated with aGVHD. Using shotgun metagenomic sequencing and a large cohort, we aimed to confirm and extend these observations. Adult aHSCT recipients with stool samples collected from day -30 to day 100 relative to aHSCT were included. One sample was selected per patient per period (pre-aHSCT (day -30 to day 0), early post-aHSCT (day 1 to day 28), and late post-aHSCT (day 29 to day 100)), resulting in 150 aHSCT recipients and 259 samples. Microbial and clinical factors were tested for differences between time periods and an association with subsequent aGVHD. Patients showed a decline in gut bacterial diversity posttransplant, with several patients developing a dominance of Enterococcus. A total of 36 recipients developed aGVHD at a median of 34 days (interquartile range, 26-50 days) post-aHSCT. Lower microbial gene richness (P = .02), a lower abundance of the genus Blautia (P = .05), and a lower abundance of Akkermansia muciniphila (P = .01) early post-aHSCT was observed in those who developed aGVHD. Myeloablative conditioning was associated with aGVHD along with a reduction in gene richness and abundance of Blautia and A muciniphila. These results confirm low diversity and Blautia being associated with aGVHD. Crucially, we add that pretransplant conditioning is associated with changes in gut microbiota. Investigations are warranted to determine the interplay of gut microbiota and conditioning in the development of aGVHD.
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http://dx.doi.org/10.1182/bloodadvances.2020002677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686902PMC
November 2020

Case Report: Hyper IgM Syndrome Identified by Whole Genome Sequencing in a Young Syrian Man Presenting With Atypical, Severe and Recurrent Mucosal Leishmaniasis.

Front Immunol 2020 11;11:567856. Epub 2020 Sep 11.

Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

A previously healthy 19-year-old Syrian man presented with atypical and severe mucosal leishmaniasis caused by . During a 2-year period, he had three severe relapses despite various treatment strategies, including liposomal amphotericin B and Miltefosine. Because of the unusual clinical presentation, potential underlying immunodeficiency was investigated. Normal T and NK cell counts were found. The B cell count was slightly elevated at 0.7 × 10 cells/L (0.09 × 10 to 0.57 × 10 cells/L), but the proportions of memory and isotype switched memory B cells were severely diminished IgG levels were low, at 309 mg/dL (610-1490 mg/dL). The initial IgM and IgA levels were within normal range, but the IgA levels decreased to 57 mg/dL (70-430 mg/dL) during follow up. Common variable immunodeficiency (CVID) was initially suspected, because the immunological results of low IgG and IgA, low switched memory B cells, no profound T cell deficiency found and absence of secondary cause of hypogammaglobulinemia were compatible with this diagnosis (ESID 2019). However, the highly unusual and severe clinical presentation of is not suggestive of B-cell deficiency or CVID. Eventually a pathogenic nonsense variant in the CD40 ligand gene [p.(Arg11)] was identified by whole genome sequencing, thus enabling the diagnosis of X-linked hyper IgM syndrome. This case illustrates and supports the potential for the use of whole genome sequencing in accurate diagnosis of primary immunodeficiencies.
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http://dx.doi.org/10.3389/fimmu.2020.567856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516301PMC
May 2021

Whole-Exome Sequencing of Patients With Recurrent HSV-2 Lymphocytic Mollaret Meningitis.

J Infect Dis 2021 May;223(10):1776-1786

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.

Recurrent lymphocytic meningitis, also referred to as Mollaret meningitis, is a rare neurological disease characterized mainly by reactivation of herpes simplex virus 2 (HSV-2) from sensory ganglia. However, the underlying host immune determinants and viral factors rendering some individuals unable to maintain HSV-2 latency are largely unknown. We collected a cohort of 15 patients diagnosed with Mollaret meningitis. By whole-exome sequencing we identified rare host genetic variants predicted to be deleterious in molecules involved in (1) ubiquitin-proteasome pathways, (2) the autophagy machinery, and (3) cell proliferation/apoptosis. Moreover, infection of patient cells with HSV-2 or stimulation by virus-derived double-stranded DNA ligands revealed reduced antiviral interferon responses in most patients. These findings may contribute to a better understanding of disease pathogenesis and protective immunity to HSV in the central nervous system, and may ultimately be of importance for identification of targets for development of improved prophylaxis and treatment of this disease.
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http://dx.doi.org/10.1093/infdis/jiaa589DOI Listing
May 2021

SARS-CoV-2 infection among patients with haematological disorders: Severity and one-month outcome in 66 Danish patients in a nationwide cohort study.

Eur J Haematol 2021 Jan 29;106(1):72-81. Epub 2020 Sep 29.

Department of Haematology, Odense University Hospital, Odense, Denmark.

Objectives: Patients with haematological disorders may be particularly vulnerable to respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, this is unknown.

Methods: We conducted a prospective, nationwide study including 66 patients in follow-up at Danish haematology departments with a malignant or non-malignant haematological disorder and with verified SARS-CoV-2 infection. Outcomes were intensive care unit (ICU) admission and one-month survival rate.

Results: Mean age was 66.7 years, 60.6% were males, 90.9% had comorbidity, and 13.6% had a BMI ≥ 30. The most frequent diagnoses were chronic lymphocytic leukaemia/lymphoma (47.0%), multiple myeloma (16.7%) and acute leukaemia/myelodysplastic syndrome (AL/MDS) (12.1%). Treatment for the haematological disease was ongoing in 59.1% of cases. Neutropenia was present in 6.5%, lymphopenia in 46.6% and hypogammaglobulinaemia in 26.3%. The SARS-CoV-2 infection was mild in 50.0%, severe in 36.4% and critical in 13.6%. After one month, 21.2% had been admitted to ICU, and 24.2% died. Mortality was highest in older patients, patients with severe/critical SARS-CoV-2 infection, high comorbidity score or high performance status score, purine analogue treatment and with AL/MDS. Although older patients and patients with comorbidities had the highest mortality rates, mortality was considerable among all haematological patients.

Conclusion: Haematological patients with SARS-CoV-2 infection has a severe clinical course.
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http://dx.doi.org/10.1111/ejh.13519DOI Listing
January 2021

Characteristics, interventions, and longer term outcomes of COVID-19 ICU patients in Denmark-A nationwide, observational study.

Acta Anaesthesiol Scand 2021 01 3;65(1):68-75. Epub 2020 Oct 3.

Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark.

Background: Most data on intensive care unit (ICU) patients with COVID-19 originate in selected populations from stressed healthcare systems with shorter term follow-up. We present characteristics, interventions and longer term outcomes of the entire, unselected cohort of all ICU patients with COVID-19 in Denmark where the ICU capacity was not exceeded.

Methods: We identified all patients with SARS-CoV-2 admitted to any Danish ICU from 10 March to 19 May 2020 and registered demographics, chronic comorbidities, use of organ support, length of stay, and vital status from patient files. Risk factors for death were analyzed using adjusted Cox regression analysis.

Results: There were 323 ICU patients with confirmed COVID-19. Median age was 68 years, 74% were men, 50% had hypertension, 21% diabetes, and 20% chronic pulmonary disease; 29% had no chronic comorbidity. Invasive mechanical ventilation was used in 82%, vasopressors in 83%, renal replacement therapy in 26%, and extra corporeal membrane oxygenation in 8%. ICU stay was median 13 days (IQR 6-22) and hospital stay 19 days (11-30). Median follow-up was 79 days. At end of follow-up, 118 had died (37%), 15 (4%) were still in hospital hereof 4 in ICU as of 16 June 2020. Risk factors for mortality included male gender, age, chronic pulmonary disease, active cancer, and number of co-morbidities.

Conclusions: In this nationwide, population-based cohort of ICU patients with COVID-19, longer term survival was high despite high age and substantial use of organ support. Male gender, age, and chronic co-morbidities, in particular chronic pulmonary disease, were associated with increased risk of death.
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http://dx.doi.org/10.1111/aas.13701DOI Listing
January 2021

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.

Acta Anaesthesiol Scand 2020 10 30;64(9):1365-1375. Epub 2020 Jul 30.

Department of Anaesthesia and Intensive Care, Odense University Hospital, Odense, Denmark.

Introduction: Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods: The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion: The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.
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http://dx.doi.org/10.1111/aas.13673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404666PMC
October 2020

Invasive aspergillosis in patients with severe COVID-19 pneumonia.

Clin Microbiol Infect 2021 01 5;27(1):147-148. Epub 2020 Aug 5.

Statens Serum Institut, Copenhagen, Denmark.

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http://dx.doi.org/10.1016/j.cmi.2020.07.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403849PMC
January 2021

Persistent COVID-19 in an Immunocompromised Patient Temporarily Responsive to Two Courses of Remdesivir Therapy.

J Infect Dis 2020 09;222(7):1103-1107

Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

The antiviral drug remdesivir has been shown clinically effective for treatment of COVID-19. We here demonstrate suppressive but not curative effect of remdesivir in an immunocompromised patient. A man in his fifties treated with chemoimmunotherapy for chronic lymphocytic leukemia experienced a 9-week course of COVID-19 with high fever and severe viral pneumonia. During two 10-day courses of remdesivir starting 24 and 45 days after fever onset, pneumonia and spiking fevers remitted, but relapsed after discontinuation. Kinetics of temperature, C-reactive protein, and lymphocyte counts mirrored the remitting/relapsing SARS-CoV-2 infection. Combination therapy or longer treatment duration may be needed in immunocompromised patients.
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http://dx.doi.org/10.1093/infdis/jiaa446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454684PMC
September 2020

The clinical spectrum of tularemia-Two cases.

IDCases 2020 27;21:e00890. Epub 2020 Jun 27.

Department of Infectious Diseases, The National University Hospital, Rigshospitalet, Denmark.

We report two cases of tularemia with different clinical manifestations, both suspected of tick-borne transmission and with near-complete remission of all symptoms within 3 months after antimicrobial treatment. The first patient presented with a classical ulceroglandular manifestation; general malaise, an ulcer and lymphadenopathy, occurring two weeks after a tick bite. Diagnosis was established by polymerase chain reaction of a skin biopsy from the ulcer. The second patient presented with a rare systemic manifestation including bacteremia and myocarditis resulting in severe clinical heart failure, pulmonary edema and secondary kidney failure. Previous tick bites were elucidated after the bacteremia was discovered. The cases underscore the heterogeneity of manifestations, the diagnostic approach and the importance of thorough medical history including recent exposures especially in cases with infection of unknown origin.
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http://dx.doi.org/10.1016/j.idcr.2020.e00890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350126PMC
June 2020

Tuberculosis among Patients Undergoing Solid Organ Transplantation or Dialysis in a Low-Endemic Country, 2004-2017.

Tuberc Res Treat 2020 25;2020:7636975. Epub 2020 Apr 25.

Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ö, Denmark.

Background: The risk of active TB among solid organ transplant (SOT) recipients and patients initiating chronic dialysis in a country with low incidence of TB is not well elucidated.

Methods: Patients aged >18 years who were transplanted with a solid organ or initiated chronic dialysis at Copenhagen University Hospital in the period 2004-2017 were followed from date of transplantation or initiation of dialysis. Data on demographics and outcomes were obtained from nationwide registries.

Results: We included 1,989 SOT recipients and 1,305 patients initiating chronic dialysis, who were followed for a total of 9,785 and 4,196 person-years (PY), respectively. Only a minority of patients had been screened for latent TB prior to SOT or initiation of dialysis. The incidence rates (IRs)/100,000 PY of TB among patients from medium/high TB endemic areas were 358 (95% CI 115-1,110) and 1,266 (95% CI 681-2354) for SOT and dialysis patients, respectively, whereas IRs among patients of Danish origin were 11 (95% CI 2-81) and 31 (95% CI 4-218).

Conclusion: The incidence of TB among immunosuppressed immigrants from medium/high TB endemic countries was very high, while the risk of TB among patients from low-endemic countries was minimal.
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http://dx.doi.org/10.1155/2020/7636975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201514PMC
April 2020

Mortality and admission to intensive care units after febrile neutropenia in patients with cancer.

Cancer Med 2020 05 7;9(9):3033-3042. Epub 2020 Mar 7.

Centre of Excellence for Health, Immunity and Infections (CHIP), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Febrile neutropenia (FN) is a critical complication of chemotherapy associated with increased in-hospital mortality. However, associations with increased mortality and intensive care unit (ICU) admissions during longer follow-up are not established. Patients treated with standard first-line chemotherapy for solid cancers at Rigshospitalet, Denmark in 2010-2016 were included. Incidence rate ratios (IRR) of all-cause, infectious and cardiovascular mortality, and ICU admissions after FN were analyzed by Poisson regression. Risk factors at the time of FN were analyzed in the subpopulation of patients with FN; all-cause mortality was further stratified by the time periods 0-30, 31-365, and 366+ days after FN. We included 9018 patients with gastric (14.4%) and breast (13.1%) cancer being the most common, 51.2% had locally advanced or disseminated disease and the patients had a median Charlson Comorbidity Index score of 0 (interquartile range, 0-0). During follow-up, 845 (9.4%) experienced FN and 4483 (49.7%) died during 18 775 person-years of follow-up. After adjustment, FN was associated with increased risk of all-cause mortality, infectious mortality, and ICU admissions with IRRs of 1.39 (95% CI, 1.24-1.56), 1.94 (95% CI, 1.43-2.62), and 2.28 (95% CI, 1.60-3.24). Among those with FN, having a positive blood culture and low lymphocytes were associated with excess risk of death and ICU admissions (predominantly the first 30 days after FN), while elevated C-reactive protein and low hemoglobin predicted mortality the first year after FN. The risk of death varied according to the time since FN; adjusted IRR per additional risk factor present for the time periods 0-30, 31-365, and 366+ days after FN were 2.00 (95% CI, 1.45-2.75), 1.36 (95% CI, 1.17-1.57), and 1.17 (95% CI, 0.98-1.41). FN was associated with increased mortality and risk of ICU admissions. An objectively identifiable subgroup of patients among those with FN carried this excess risk.
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http://dx.doi.org/10.1002/cam4.2955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196064PMC
May 2020

Richter's transformation in patients with chronic lymphocytic leukaemia: a Nationwide Epidemiological Study.

Leuk Lymphoma 2020 06 7;61(6):1435-1444. Epub 2020 Feb 7.

Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Approximately, 2-10% of patients with CLL develop RT, most often as diffuse large B-cell lymphoma. To assess the incidence of RT, we examined risk factors for RT and death among patients with RT in a nationwide CLL cohort (from 2008 to 2016). Among 3772 patients, 113 had biopsy-proven RT. With a median follow-up of 4.3 years, the 5-year cumulative incidence of RT was 2.8%. Advanced Binet stage (B/C) (<.001), unmutated IGHV (<.001), and del(17p) (<.001) were independently associated with risk of developing RT. Half of the patients with RT (49%) were treatment-naïve prior to transformation and demonstrated longer survival after RT compared to patients previously treated for CLL (6.1 vs. 2.8 years, =.03). Whether this finding could be explained by a higher proportion of clonally unrelated RT among treatment-naïve patients, remain to be addressed.
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http://dx.doi.org/10.1080/10428194.2020.1719092DOI Listing
June 2020

Rezafungin Activity against Contemporary Nordic Clinical Isolates and Determined by the EUCAST Reference Method.

Antimicrob Agents Chemother 2020 03 24;64(4). Epub 2020 Mar 24.

Unit for Mycology, Statens Serum Institut, Copenhagen, Denmark

Rezafungin (formerly CD101) is a novel echinocandin in clinical development. EUCAST epidemiological cutoff values (ECOFFs) have not yet been established. We determined the activity of rezafungin and comparators against 1,293 Nordic yeast isolates and 122 Indian isolates and established single-center wild-type upper limits (WT-UL). The isolates (19 spp. and 13 other yeast species) were identified using Chromagar; matrix-assisted laser desorption ionization-time of flight (MALDI-TOF); and, when needed, internal transcribed spacer sequencing. EUCAST E.Def 7.3.1 susceptibility testing included rezafungin, anidulafungin, micafungin, amphotericin B, and fluconazole. WT-UL were established following EUCAST principles for visual and statistical ECOFF setting. target genes were sequenced for rezafungin non-wild-type isolates. EUCAST clinical breakpoints for fungi version 9.0 were adopted for susceptibility classification. Rezafungin had species-specific activity similar to that of anidulafungin and micafungin. On a milligram-per-liter basis, rezafungin was overall less active than anidulafungin and micafungin but equally or more active than fluconazole and amphotericin B against the most common species, except We identified 37 (3.1%) rezafungin non-wild-type isolates of (1.9%), (3.0%), (2.7%), (2.9%), (1.2%), and (14.8%). Alterations in Fks hot spots were found in 26/26 Nordic and 8/18 non-wild-type isolates. Rezafungin displayed broad activity against spp., including Adopting WT-UL established here, few Nordic strains, but a significant proportion of isolates, had elevated MICs with mutations in target genes that conferred echinocandin cross-resistance. mutations raised rezafungin MICs notably less than anidulafungin and micafungin MICs in .
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http://dx.doi.org/10.1128/AAC.02438-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179313PMC
March 2020

Evaluation of an electronic, patient-focused management system aimed at preventing cytomegalovirus disease following solid organ transplantation.

Transpl Infect Dis 2020 Apr 10;22(2):e13252. Epub 2020 Feb 10.

Department of Infectious Diseases, Centre of Excellence for Health, Immunity and Infections (CHIP), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Cytomegalovirus (CMV) infection is common among solid organ transplant (SOT) recipients and may cause CMV disease. To optimize the implementation of existing prevention strategies, the Management of Post-transplant Infections in Collaborating Hospitals (MATCH) program was developed. Two key performances of MATCH (diagnosing CMV infection at low viral load (VL) and before the onset of CMV disease) were assessed prior to, during and after the implementation of MATCH.

Methods: The MATCH program included a personalized surveillance plan, prophylaxis and preemptive therapy determined by the recipient's risk of CMV infection. The plan was composed through predefined algorithms and implemented through harvesting of real-time data from medical records. Risk of CMV disease was compared for recipients transplanted during and after vs prior to the implementation of MATCH. Lung and non-lung transplants were analyzed separately.

Results: A total of 593, 349, 520, and 360 SOT recipients were transplanted before (2007-2010), during (2011-2012), early after (2013-2015), and late after (2016-2017) implementation of MATCH with an observed reduction of diagnostic VL (P < .001) over time. Risk of CMV disease was reduced among non-lung transplant recipients transplanted during (adjusted hazard ratios [95% CI] 0.15 [0.04-0.54], P = .003), early after (aHR 0.27 [0.11-0.63], P = .003), and late after (aHR 0.17 [0.06-0.52], P = .002) compared with prior to MATCH. No significant change was observed among lung transplants.

Conclusion: Implementation of CMV preventive strategies through MATCH was associated with a reduced risk of CMV disease among non-lung transplant recipients. Furthermore, the limitations of VL as a sole indicator for CMV disease in lung transplants were emphasized.
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http://dx.doi.org/10.1111/tid.13252DOI Listing
April 2020

Bacillary angiomatosis in a solid organ transplant recipient.

Authors:
Marie Helleberg

IDCases 2019 31;18:e00649. Epub 2019 Oct 31.

Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Denmark.

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http://dx.doi.org/10.1016/j.idcr.2019.e00649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889470PMC
October 2019

Cutaneous leishmaniasis with secondary mucosal disease in a traveller due to Leishmania (Viannia) braziliensis.

J Travel Med 2020 Feb;27(1)

Department of Infectious Diseases, Rigshospitalet - University of Copenhagen, 8632 København, Denmark.

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http://dx.doi.org/10.1093/jtm/taz093DOI Listing
February 2020

Gut microbiome comparability of fresh-frozen versus stabilized-frozen samples from hospitalized patients using 16S rRNA gene and shotgun metagenomic sequencing.

Sci Rep 2019 09 16;9(1):13351. Epub 2019 Sep 16.

PERSIMUNE Centre of Excellence, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark.

Collection of faecal samples for microbiome analysis in acutely sick patients is logistically difficult, particularly if immediate freezing is required (i.e. fresh-frozen, or FF sampling). Previous studies in healthy/non-hospitalized volunteers have shown that chemical stabilization (i.e. stabilized-frozen, or SF sampling) allows room-temperature storage with comparable results to FF samples. To test this in a hospital setting we compared FF and SF approaches across 17 patients undergoing haematopoietic stem cell transplantation (HSCT) using both 16S rRNA gene and shotgun metagenomic sequencing. A paired (same stool specimen) comparison of FF and SF samples was made, with an overall comparable level in relative taxonomic abundances between the two sampling techniques. Though shotgun metagenomic sequencing found significant differences for certain bacterial genera (P < 0.001), these were considered minor methodological effects. Within-sample diversity of either method was not significantly different (Shannon diversity P = 0.68 and P = 0.89) and we could not reject the null hypothesis that between-sample variation in FF and SF were equivalent (P = 0.98 and P = 1.0). This indicates that SF samples can be used to reliably study the microbiome in acutely sick patient populations, thus creating and enabling further outcomes-based metagenomic studies on similarly valuable cohorts.
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http://dx.doi.org/10.1038/s41598-019-49956-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746779PMC
September 2019