Meropenem pharmacokinetic/pharmacodynamic target attainment and clinical response in ICU patients: A prospective observational study.

BACKGROUND: Several studies report lack of meropenem pharmacokinetic/pharmacodynamic (PK/PD) target attainment (TA) and risk of therapeutic failure with intermittent bolus infusions in intensive care unit (ICU) patients. The aim of this study was to describe meropenem TA in an ICU population and the clinical response in the first 72 h after therapy initiation. METHODS: A prospective observational study of ICU patients ≥18 years was conducted from 2014 to 2017. Patients with normal renal clearance (NRC) and augmented renal clearance (ARC) and patients on continuous renal replacement therapy (CRRT) were included. Meropenem was administered as intermittent bolus infusions, mainly at a dose of 1 g q6h. Peak, mid, and trough levels were sampled at 24, 48, and 72 h after therapy initiation. TA was defined as 100% T > 4× MIC or trough concentration above 4× MIC. Meropenem PK was estimated using traditional calculation methods and population pharmacokinetic modeling (P-metrics®). Clinical response was evaluated by change in C-reactive protein (CRP), Sequential Organ Failure Assessment (SOFA) score, leukocyte count, and defervescence. RESULTS: Eighty-seven patients were included, with a median Simplified Acute Physiology (SAPS) II score 37 and 90 days mortality rate of 32%. Median TA was 100% for all groups except for the ARC group with 45.5%. Median CRP fell from 175 (interquartile range [IQR], 88-257) to 70 (IQR, 30-114) (p < .001) in the total population. A reduction in SOFA score was observed only in the non-CRRT groups (p < .001). CONCLUSION: Intermittent meropenem bolus infusion q6h gives satisfactory TA in an ICU population with variable renal function and CRRT modality, except for ARC patients. No consistent relationship between TA and clinical endpoints were observed.

Raised Serum Markers of T Cell Activation and Exhaustion in Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency.

PURPOSE: About 20-30% of patients with common variable immunodeficiency (CVID) develop granulomatous-lymphocytic interstitial lung disease (GLILD) as one of several non-infectious complications to their immunodeficiency. The purpose of this study was to identify biomarkers that could distinguish GLILD from other non-infectious complications in CVID. METHODS: We analyzed serum biomarkers related to inflammation, pulmonary epithelium injury, fibrogenesis, and extracellular matrix (ECM) remodeling, and compared three subgroups of CVID: GLILD patients (n = 16), patients with other non-infectious complications (n = 37), and patients with infections only (n = 20). RESULTS: We found that GLILD patients had higher levels of sCD25, sTIM-3, IFN-γ, and TNF, reflecting T cell activation and exhaustion, compared to both CVID patients with other inflammatory complications and CVID with infections only. GLILD patients also had higher levels of SP-D and CC16, proteins related to pulmonary epithelium injury, as well as the ECM remodeling marker MMP-7, than patients with other non-infectious complications. CONCLUSION: GLILD patients have elevated serum markers of T cell activation and exhaustion, pulmonary epithelium injury, and ECM remodeling, pointing to potentially important pathways in GLILD pathogenesis, novel targets for therapy, and promising biomarkers for clinical evaluation of these patients.

A Nationwide Study of GATA2 Deficiency in Norway-the Majority of Patients Have Undergone Allo-HSCT.

PURPOSE: GATA2 deficiency is a rare primary immunodeficiency that has become increasingly recognized due to improved molecular diagnostics and clinical awareness. The only cure for GATA2 deficiency is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The inconsistency of genotype-phenotype correlations makes the decision regarding "who and when" to transplant challenging. Despite considerable morbidity and mortality, the reported proportion of patients with GATA2 deficiency that has undergone allo-HSCT is low (~ 35%). The purpose of this study was to explore if detailed clinical, genetic, and bone marrow characteristics could predict end-point outcome, i.e., death and allo-HSCT. METHODS: All medical genetics departments in Norway were contacted to identify GATA2 deficient individuals. Clinical information, genetic variants, treatment, and outcome were subsequently retrieved from the patients' medical records. RESULTS: Between 2013 and 2020, we identified 10 index cases or probands, four additional symptomatic patients, and no asymptomatic patients with germline GATA2 variants. These patients had a diverse clinical phenotype dominated by cytopenia (13/14), myeloid neoplasia (10/14), warts (8/14), and hearing loss (7/14). No valid genotype-phenotype correlations were found in our data set, and the phenotypes varied also within families. We found that 11/14 patients (79%), with known GATA2 deficiency, had already undergone allo-HSCT. In addition, one patient is awaiting allo-HSCT. The indications to perform allo-HSCT were myeloid neoplasia, disseminated viral infection, severe obliterating bronchiolitis, and/or HPV-associated in situ carcinoma. Two patients died, 8 months and 7 years after allo-HSCT, respectively. CONCLUSION: Our main conclusion is that the majority of patients with symptomatic GATA2 deficiency will need allo-HSCT, and a close surveillance of these patients is important to find the "optimal window" for allo-HSCT. We advocate a more offensive approach to allo-HSCT than previously described.

Elevated plasma sTIM-3 levels in patients with severe COVID-19.

BACKGROUND: The pathogenesis of coronavirus disease 2019 (COVID-19) is still incompletely understood, but it seems to involve immune activation and immune dysregulation. OBJECTIVE: We examined the parameters of activation of different leukocyte subsets in COVID-19-infected patients in relation to disease severity. METHODS: We analyzed plasma levels of myeloperoxidase (a marker of neutrophil activation), soluble (s) CD25 (sCD25) and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T-cell activation and exhaustion), and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19-infected patients at hospital admission and 2 additional times during the first 10 days in relation to their need for intensive care unit (ICU) treatment. RESULTS: Our major findings were as follows: (1) severe clinical outcome (ICU treatment) was associated with high plasma levels of sTIM-3 and myeloperoxidase, suggesting activated and potentially exhausted T cells and activated neutrophils, respectively; (2) in contrast, sCD14 and sCD163 showed no association with need for ICU treatment; and (3) levels of sCD25, sTIM-3, and myeloperoxidase were inversely correlated with degree of respiratory failure, as assessed by the ratio of Pao2 to fraction of inspired oxygen, and were positively correlated with the cardiac marker N-terminal pro-B-type natriuretic peptide. CONCLUSION: Our findings suggest that neutrophil activation and, in particular, activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T-cell-targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder.

The use of eculizumab in Capnocytophaga canimorsus associated thrombotic microangiopathy: a case report.

BACKGROUND: The use of complement inhibition is well established for complement mediated thrombotic microangiopathy, but its role in secondary forms of thrombotic microangiopathy is debated. We here present a case of thrombotic microangiopathy triggered by Capnocytophaga canimorsus, illustrating the diagnostic difficulties in discriminating between different thrombotic microangiopathies, and the dilemmas regarding how to treat this disease entity. CASE PRESENTATION: A previously healthy 56-year-old woman presented with fever and confusion. She was diagnosed with sepsis from Capnocytophaga canimorsus and thrombotic microangiopathy. Marked activation of both T-cells, endothelium and complement were documented. She was successfully treated with antimicrobial therapy, the complement inhibitor eculizumab and splenectomy. After several weeks, a heterozygote variant in complement factor B was localized, potentially implying the diagnosis of a complement mediated TMA over an isolated infection related TMA. CONCLUSIONS: We discuss the possible interactions between complement activation and other findings in severe infection and argue that complement inhibition proved beneficial to this patient's rapid recovery.

Factors increasing the risk of inappropriate vancomycin therapy in ICU patients: A prospective observational study.

BACKGROUND: Vancomycin trough levels are frequently subtherapeutic in intensive care unit (ICU) patients. The aim of this study was to identify patients at risk of therapeutic failure defined as vancomycin area-under-the-curve0-24 /minimum inhibitory concentration (AUC0-24 /MIC) <400, and to examine possible effects of different MICs, the variability in renal clearance and continuous renal replacement therapy (CRRT), and the relevance of vancomycin therapy. METHODS: A prospective observational study of ICU patients ≥ 18 years at initiation of vancomycin therapy was conducted from May 2013 to October 2015. The patients were divided into four groups according to renal function and CRRT-mode as follows: normal- or augmented renal clearance and continuous venovenous hemodialysis or -hemofiltration. Vancomycin peak and trough levels were measured at 24, 48, and 72 hours after therapy initiation. Relevance of vancomycin therapy was retrospectively evaluated based on microbiological results. RESULTS: Eighty-three patients were included, median age 54.5 years, 74.5% male, SAPS II score 46, and 90 day mortality 28%. Vancomycin therapy was initiated on ICU-day 8 (IQR, 5-12), with a median treatment time of 7.5 (IQR, 5-12) days. AUC0-24 /MIC > 400 was reached in 81% and 8% with MIC = 1 and 2 mg/L respectively. The CRRT groups had higher AUC0-24 /MIC-ratios than the non-CRRT groups (P < .001). Augmented renal clearance increased the risk of AUC0-24 /MIC < 400, independent of MIC-value. Initiation of vancomycin therapy was retrospectively considered relevant in 28 patients (34%). CONCLUSION: A MIC-value >1 mg/L and augmented renal clearance, were factors increasing the risk of therapeutic failure. Vancomycin treatments could have been omitted or shortened in most of these patients.

A man in his thirties with right ventricular heart failure, jaundice and abdominal pain. / En mann i 30-årene med høyresidig hjertesvikt, ikterus og magesmerter.

BACKGROUND: The combination of jaundice and acute abdominal pain is a common clinical problem associated with a broad array of aetiologies. CASE PRESENTATION: A 36-year-old male with Down's syndrome and Eisenmenger's syndrome presented with abdominal pain, jaundice and acute liver failure. Initial transabdominal ultrasound and subsequent magnetic resonance cholangiopancreatography (MRCP) revealed gallbladder stones, but no common bile duct stones. During the course of the patient's hospital admission, his liver chemistries were consistently elevated. Thus, endoscopic retrograde cholangiography (ERC) with sphincterotomy was performed, despite the anaesthesiological risk associated with his chronic heart failure. However, the ERC and sphincterotomy did not relieve the patient's symptoms and had no apparent effect on his abnormal liver chemistries. By the end of his hospital stay, the patient recovered spontaneously and was discharged with no final conclusion having been reached. An unexpected turn of events led us to conclude upon a diagnosis a few weeks later. INTERPRETATION: This case illustrates the challenges of a multidisciplinary approach in a complex patient, and an overlooked detail that became a lesson to learn from.

Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells.

Heterozygous GATA2 mutation is associated with immunodeficiency, lymphedema, and myelodysplastic syndrome. Disease presentation is variable, often coinciding with loss of circulating dendritic cells, monocytes, B cells, and natural killer (NK) cells. Nonetheless, in a proportion of patients carrying GATA2 mutation, NK cells persist. We found that peripheral blood NK cells in symptomatic patients uniformly lacked expression of the transcription factor promyelocytic leukemia zinc finger (PLZF), as well as expression of intracellular signaling proteins FcεRγ, spleen tyrosine kinase (SYK), and EWS/FLI1-Activated Transcript 2 (EAT-2) in a variegated manner. Moreover, consistent with an adaptive identity, NK cells from patients with GATA2 mutation displayed altered expression of cytotoxic granule constituents and produced interferon-γ upon Fc-receptor engagement but not following combined interleukin-12 (IL-12) and IL-18 stimulation. Canonical, PLZF-expressing NK cells were retained in asymptomatic carriers of GATA2 mutation. Developmentally, GATA-binding protein-2 (GATA-2) was expressed in hematopoietic stem cells, but not in NK-cell progenitors, CD3-CD56bright, canonical, or adaptive CD3-CD56dim NK cells. Peripheral blood NK cells from individuals with GATA2 mutation proliferated normally in vitro, whereas lineage-negative progenitors displayed impaired NK-cell differentiation. In summary, adaptive NK cells can persist in patients with GATA2 mutation, even after NK-cell progenitors expire. Moreover, our data suggest that adaptive NK cells are more long-lived than canonical, immunoregulatory NK cells.

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

Differences in epidemiology of candidaemia in the Nordic countries - what is to blame?

National data from Denmark, Finland, Norway and Sweden demonstrate remarkable differences in candidaemia epidemiology. Only Denmark has reported a high incidence of 10 per 100 000 inhabitants and a species shift towards increased C. glabrata candidaemias. The reasons for this development remain unclear. The aim of this study was to explore possible contributing factors for the differences in Candida epidemiology in the Nordic countries. We used public data from 2011 from Denmark, Finland, Norway and Sweden on epidemiology, demographics, health facilities, predisposing risk factors, consumption of antimicrobial drugs and fungicides in agricultural industry. Only the prevalence of haematological malignancies (P < 0.001) was significantly higher in Denmark compared to the other Nordic countries. The antibacterial drug use of metronidazole, piperacillin-tazobactam, ciprofloxacin, colistin and carbapenems, and antifungal use of fluconazole in humans (P < 0.001), were significantly higher in Denmark compared to the other Nordic countries (all P < 0.001). Our findings suggest haematological malignancy, the use of certain antibacterial drugs and azoles in humans as possible contributing factors for the differences in Candida epidemiology. However, our results should be interpreted with caution due to the lack of long-term, case-specific data. Further studies are needed.

Hemophagocytic lymphohistiocytosis in leprosy.

A patient from Southeast Asia was diagnosed with systemic lupus erythematosus. One year later, she experienced exacerbation of skin lesions and was diagnosed with erythema nodosum leprosum. Upon treatment, the patient developed hemophagocytic lymphohistiocytosis with multi-organ failure and died from invasive fungal infection. Hemophagocytic lymphohistiocytosis has to our knowledge, not previously been reported in leprosy.

Diagnostics, treatment and outcomes of cardiac sarcoidosis in a Norwegian cohort.

BACKGROUND: Evidence-based guidelines for cardiac sarcoidosis (CS) regarding use of second- and third-line agents, treatment duration, surveillance and prognostic factors are lacking. OBJECTIVE: To analyze the clinical presentation, diagnostics, treatment, monitoring and clinical outcomes in a Norwegian cohort. METHODS: Using discharge diagnoses between 2017 through 2020 from a large tertiary center, we identified 52 patients with CS. We performed a systematic chart review following a pre-specified checklist. The primary outcome of major cardiovascular events (MACE) was defined as a composite of cardiovascular hospitalization, defibrillator therapy, cardiac transplantation, or death. RESULTS: 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed pathological tracer uptake in 35/36 (97%) of immunosuppression-naïve patients. Immunosuppressive treatment was administered to 49/52 patients (94%) for a median of 43 (IQR 34) months; 69% were treated with second-line (methotrexate, azathioprine, mycophenolate mofetil) and 25% with third-line (rituximab, infliximab) agents, respectively. Rituximab reduced inflammation as assessed by interval FDG-PET imaging and was overall well tolerated. Median duration to first MACE was 6 (IQR 10) months and 17/23 patients (74%) experienced a MACE within 12 months from CS diagnosis. No mortality was recorded and 20% achieved full remission. Age below the median of 53 years at time of diagnosis was associated with an increased risk of a MACE. CONCLUSION: Long-term immunosuppression including a liberal use of non-steroidal agents, appeared essential in treating CS. Although the burden of cardiovascular events was substantial, the survival was excellent in this contemporary cohort. Prospective randomized studies are urgently needed to define the best therapy for these patients.

Case report: A prosthetic valve endocarditis caused by Legionella bozemanae in an immunocompetent patient.

Extrapulmonary infections with Legionella species are rare, but important to acknowledge. We report a case of infective endocarditis (IE) with Legionella bozemanae in a 66-year-old immunocompetent man with an aortic homograft. The diagnosis was made by direct 16S rRNA gene amplification from valve material, confirmed by a targeted Legionella-PCR in serum and the detection of L. bozemanae specific antibodies. To our knowledge, this is the first confirmed case of IE with L. bozemanae as causative pathogen. The infected aortic prosthesis was replaced by a homograft, and the patient was successfully treated with levofloxacin and azithromycin for 6 weeks.

Corticosteroids and superinfections in COVID-19 patients on invasive mechanical ventilation.

OBJECTIVES: To determine the incidence and characteristics of superinfections in mechanically ventilated COVID-19 patients, and the impact of dexamethasone as standard therapy. METHODS: This multicentre, observational, retrospective study included patients ≥ 18 years admitted from March 1st 2020 to January 31st 2021 with COVID-19 infection who received mechanical ventilation. Patient characteristics, clinical characteristics, therapy and survival were examined. RESULTS: 155/156 patients (115 men, mean age 62 years, range 26-84 years) were included. 67 patients (43%) had 90 superinfections, pneumonia dominated (78%). Superinfections were associated with receiving dexamethasone (66% vs 32%, p<0.0001), autoimmune disease (18% vs 5.7%, p<0.016) and with longer ICU stays (26 vs 17 days, p<0,001). Invasive fungal infections were reported exclusively in dexamethasone-treated patients [8/67 (12%) vs 0/88 (0%), p<0.0001]. Unadjusted 90-day survival did not differ between patients with or without superinfections (64% vs 73%, p=0.25), but was lower in patients receiving dexamethasone versus not (58% vs 78%, p=0.007). In multiple regression analysis, superinfection was associated with dexamethasone use [OR 3.7 (1.80-7.61), p<0.001], pre-existing autoimmune disease [OR 3.82 (1.13-12.9), p=0.031] and length of ICU stay [OR 1.05 p<0.001]. CONCLUSIONS: In critically ill COVID-19 patients, dexamethasone as standard of care was strongly and independently associated with superinfections.