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1.
Emerg Infect Dis ; 27(11): 2892-2898, 2021 11.
Article in English | MEDLINE | ID: covidwho-1551452

ABSTRACT

We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease-associated pulmonary aspergillosis (CAPA). We found 10%-15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%-52%.


Subject(s)
COVID-19 , Invasive Pulmonary Aspergillosis , Pulmonary Aspergillosis , Cohort Studies , Humans , SARS-CoV-2
2.
J Clin Microbiol ; 59(12): e0122921, 2021 11 18.
Article in English | MEDLINE | ID: covidwho-1522903

ABSTRACT

The literature regarding COVID-19-associated pulmonary aspergillosis (CAPA) has shown conflicting observations, including survival of CAPA patients not receiving antifungal therapy and discrepancy between CAPA diagnosis and autopsy findings. To gain insight into the pathophysiology of CAPA, we performed a case-control study in which we compared Aspergillus test profiles in CAPA patients and controls in relation to intensive care unit (ICU) mortality. This was a multinational case-control study in which Aspergillus test results, use of antifungal therapy, and mortality were collected from critically ill COVID-19 patients. Patients were classified using the 2020 European Confederation for Medical Mycology and the International Society for Human and Animal Mycology (ECMM/ISHAM) consensus case definitions. We analyzed 219 critically ill COVID-19 cases, including 1 proven, 38 probable, 19 possible CAPA cases, 21 Aspergillus-colonized patients, 7 patients only positive for serum (1,3)-ß-d-glucan (BDG), and 133 cases with no evidence of CAPA. Mortality was 53.8% in CAPA patients compared to 24.1% in patients without CAPA (P = 0.001). Positive serum galactomannan (GM) and BDG were associated with increased mortality compared to serum biomarker-negative CAPA patients (87.5% versus 41.7%, P = 0.046; 90.0% versus 42.1%, P = 0.029, respectively). For each point increase in GM or 10-point BDG serum concentration, the odds of death increased (GM, odds ratio [OR] 10.208, 95% confidence interval [CI], 1.621 to 64.291, P = 0.013; BDG, OR, 1.247, 95% CI, 1.029 to 1.511, P = 0.024). CAPA is a complex disease, probably involving a continuum of respiratory colonization, tissue invasion, and angioinvasion. Serum biomarkers are useful for staging CAPA disease progression and, if positive, indicate angioinvasion and a high probability of mortality. There is need for a biomarker that distinguishes between respiratory tract colonization and tissue-invasive CAPA disease.


Subject(s)
COVID-19 , Invasive Pulmonary Aspergillosis , Animals , Aspergillus , Case-Control Studies , Critical Illness , Humans , Invasive Pulmonary Aspergillosis/diagnosis , Mannans , SARS-CoV-2
3.
Emerg Infect Dis ; 27(11): 2892-2898, 2021 11.
Article in English | MEDLINE | ID: covidwho-1406813

ABSTRACT

We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease-associated pulmonary aspergillosis (CAPA). We found 10%-15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%-52%.


Subject(s)
COVID-19 , Invasive Pulmonary Aspergillosis , Pulmonary Aspergillosis , Cohort Studies , Humans , SARS-CoV-2
4.
Biosci Rep ; 41(7)2021 07 30.
Article in English | MEDLINE | ID: covidwho-1290282

ABSTRACT

Patients with sepsis display increased concentrations of sTREM-1 (soluble Triggering Receptor Expressed on Myeloid cells 1), and a phase II clinical trial focusing on TREM-1 modulation is ongoing. We investigated whether sTREM-1 circulating concentrations are associated with the outcome of patients with coronavirus disease 2019 (COVID-19) to assess the role of this pathway in COVID-19. This observational study was performed in two independent cohorts of patients with COVID-19. Plasma concentrations of sTREM-1 were assessed after ICU admission (pilot cohort) or after COVID-19 diagnosis (validation cohort). Routine laboratory and clinical parameters were collected from electronic patient files. Results showed sTREM-1 plasma concentrations were significantly elevated in patients with COVID-19 (161 [129-196] pg/ml) compared to healthy controls (104 [75-124] pg/ml; P<0.001). Patients with severe COVID-19 needing ICU admission displayed even higher sTREM-1 concentrations compared to less severely ill COVID-19 patients receiving clinical ward-based care (235 [176-319] pg/ml and 195 [139-283] pg/ml, respectively, P = 0.017). In addition, higher sTREM-1 plasma concentrations were observed in patients who did not survive the infection (326 [207-445] pg/ml) compared to survivors (199 [142-278] pg/ml, P<0.001). Survival analyses indicated that patients with higher sTREM-1 concentrations are at higher risk for death (hazard ratio = 3.3, 95%CI: 1.4-7.8). In conclusion, plasma sTREM-1 concentrations are elevated in patients with COVID-19, relate to disease severity, and discriminate between survivors and non-survivors. This suggests that the TREM-1 pathway is involved in the inflammatory reaction and the disease course of COVID-19, and therefore may be considered as a therapeutic target in severely ill patients with COVID-19.


Subject(s)
COVID-19/diagnosis , Triggering Receptor Expressed on Myeloid Cells-1/blood , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/mortality , COVID-19/virology , Case-Control Studies , Female , Healthy Volunteers , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Retrospective Studies , Risk Assessment/methods , SARS-CoV-2/isolation & purification , Severity of Illness Index , Survival Analysis
5.
Journal of the Endocrine Society ; 5(Supplement_1):A835-A836, 2021.
Article in English | PMC | ID: covidwho-1221835

ABSTRACT

Background: Lymphopenia is a key feature of immune dysfunction in bacterial sepsis and COVID-19 patients and is associated with poor clinical outcomes, but the cause is largely unknown. These severely ill patients may also present with thyroid function abnormalities, so-called non-thyroidal illness syndrome (NTIS), and several studies have suggested that TSH, thyroxin (T4) and triiodothyronine (T3) play a crucial role in the homeostatic regulation and function of lymphocyte populations.

6.
J Clin Endocrinol Metab ; 106(7): 1994-2009, 2021 06 16.
Article in English | MEDLINE | ID: covidwho-1133638

ABSTRACT

CONTEXT: Lymphopenia is a key feature of immune dysfunction in patients with bacterial sepsis and coronavirus disease 2019 (COVID-19) and is associated with poor clinical outcomes, but the cause is largely unknown. Severely ill patients may present with thyroid function abnormalities, so-called nonthyroidal illness syndrome, and several studies have linked thyrotropin (thyroid stimulating hormone, TSH) and the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3) to homeostatic regulation and function of lymphocyte populations. OBJECTIVE: This work aimed to test the hypothesis that abnormal thyroid function correlates with lymphopenia in patients with severe infections. METHODS: A retrospective analysis of absolute lymphocyte counts, circulating TSH, T4, free T4 (FT4), T3, albumin, and inflammatory biomarkers was performed in 2 independent hospitalized study populations: bacterial sepsis (n = 224) and COVID-19 patients (n = 161). A subgroup analysis was performed in patients with severe lymphopenia and normal lymphocyte counts. RESULTS: Only T3 significantly correlated (ρ = 0.252) with lymphocyte counts in patients with bacterial sepsis, and lower concentrations were found in severe lymphopenic compared to nonlymphopenic patients (n = 56 per group). Severe lymphopenic COVID-19 patients (n = 17) showed significantly lower plasma concentrations of TSH, T4, FT4, and T3 compared to patients without lymphopenia (n = 18), and demonstrated significantly increased values of the inflammatory markers interleukin-6, C-reactive protein, and ferritin. Remarkably, after 1 week of follow-up, the majority (12 of 15) of COVID-19 patients showed quantitative recovery of their lymphocyte numbers, whereas TSH and thyroid hormones remained mainly disturbed. CONCLUSION: Abnormal thyroid function correlates with lymphopenia in patients with severe infections, like bacterial sepsis and COVID-19, but future studies need to establish whether a causal relationship is involved.


Subject(s)
COVID-19/complications , Euthyroid Sick Syndromes/diagnosis , Lymphopenia/immunology , Sepsis/complications , Aged , Aged, 80 and over , COVID-19/blood , COVID-19/immunology , Euthyroid Sick Syndromes/blood , Euthyroid Sick Syndromes/immunology , Female , Greece , Humans , Lymphocyte Count , Lymphopenia/blood , Lymphopenia/diagnosis , Male , Netherlands , Retrospective Studies , SARS-CoV-2/immunology , Sepsis/blood , Sepsis/immunology , Thyroid Hormones/blood , Thyroid Hormones/immunology , Thyrotropin/blood , Thyrotropin/immunology
7.
J Infect Dis ; 223(2): 214-224, 2021 02 03.
Article in English | MEDLINE | ID: covidwho-1081282

ABSTRACT

BACKGROUND: Excessive activation of immune responses in coronavirus disease 2019 (COVID-19) is considered to be related to disease severity, complications, and mortality rate. The complement system is an important component of innate immunity and can stimulate inflammation, but its role in COVID-19 is unknown. METHODS: A prospective, longitudinal, single center study was performed in hospitalized patients with COVID-19. Plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) were assessed at baseline and during hospital admission. In parallel, routine laboratory and clinical parameters were collected from medical files and analyzed. RESULTS: Complement factors C3a, C3c, and TCC were significantly increased in plasma of patients with COVID-19 compared with healthy controls (P < .05). These complement factors were especially elevated in intensive care unit patients during the entire disease course (P < .005 for C3a and TCC). More intense complement activation was observed in patients who died and in those with thromboembolic events. CONCLUSIONS: Patients with COVID-19 demonstrate activation of the complement system, which is related to disease severity. This pathway may be involved in the dysregulated proinflammatory response associated with increased mortality rate and thromboembolic complications. Components of the complement system might have potential as prognostic markers for disease severity and as therapeutic targets in COVID-19.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , SARS-CoV-2/immunology , Aged , Aged, 80 and over , COVID-19/mortality , Complement C3c/immunology , Cytokines/blood , Disease Progression , Female , Humans , Immunity, Innate , Inflammation/immunology , Longitudinal Studies , Male , Middle Aged , Mortality , Netherlands/epidemiology , Prospective Studies , Respiratory Distress Syndrome/immunology , Severity of Illness Index
8.
J Infect Dis ; 223(8): 1322-1333, 2021 04 23.
Article in English | MEDLINE | ID: covidwho-1057852

ABSTRACT

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Immunity, Innate/immunology , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/immunology , Female , Humans , Inflammation/blood , Inflammation/immunology , Inflammation/virology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , Lymphopenia/blood , Lymphopenia/immunology , Lymphopenia/virology , Male , Middle Aged , SARS-CoV-2/immunology , Severity of Illness Index
9.
Int J Obes (Lond) ; 45(3): 687-694, 2021 03.
Article in English | MEDLINE | ID: covidwho-1047947

ABSTRACT

BACKGROUND/OBJECTIVES: Obesity appears to be an independent risk factor for ICU admission and a severe disease course in COVID-19 patients. An aberrant inflammatory response and impaired respiratory function have been suggested as underlying mechanisms. We investigated whether obesity is associated with differences in inflammatory, respiratory, and clinical outcome parameters in critically ill COVID-19 patients. SUBJECTS/METHODS: Sixty-seven COVID-19 ICU patients were divided into obese (BMI ≥ 30 kg/m2, n = 18, 72% class I obesity, 28% class II obesity) and non-obese (BMI < 30 kg/m2, n = 49) groups. Concentrations of circulating interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, and IL-1 receptor antagonist (RA) were determined from ICU admission until 10 days afterward, and routine laboratory and clinical parameters were collected. RESULTS: BMI was 32.6 [31.2-34.5] and 26.0 [24.4-27.7] kg/m2 in the obese and non-obese group, respectively. Apart from temperature, which was significantly lower in obese patients (38.1 [36.9-38.9] vs. 38.7 [38.0 -39.5] °C, p = 0.02), there were no between-group differences on ICU admission. Plasma cytokine concentrations declined over time (p < 0.05 for all), but no differences between obese and non-obese patients were observed. Also, BMI did not correlate with the cytokine response (IL-6 r = 0.09, p = 0.61, TNF-α r = 0.03, p = 0.99, IP-10 r = 0.28, p = 0.11). The kinetics of clinical inflammatory parameters and respiratory mechanics were also similar in both groups. Finally, no differences in time on ventilator, ICU length of stay or 40-day mortality between obese and non-obese patients were apparent. CONCLUSIONS: In COVID-19 patients requiring mechanical ventilation in the ICU, a higher BMI is not related to a different immunological response, unfavorable respiratory mechanics, or impaired outcome.


Subject(s)
COVID-19 , Obesity/complications , Aged , Body Mass Index , COVID-19/complications , COVID-19/epidemiology , COVID-19/immunology , COVID-19/mortality , Critical Illness , Cytokines/blood , Female , Humans , Male , Middle Aged , Prospective Studies
10.
Crit Care ; 24(1): 688, 2020 12 10.
Article in English | MEDLINE | ID: covidwho-967530

ABSTRACT

BACKGROUND: A subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation. METHODS: In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day - 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment. RESULTS: Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) (p = 0.0002), ferritin (p = 0.009), and temperature (p = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature (p = 0.03), white blood cell counts (p = 0.02), and plasma levels of ferritin (p = 0.003), procalcitonin (p = 0.001), creatinine (p = 0.01), and bilirubin (p = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results. CONCLUSIONS: Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.


Subject(s)
COVID-19/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Receptors, Interleukin-1/antagonists & inhibitors , Aged , COVID-19/physiopathology , Cohort Studies , Critical Illness/therapy , Female , Humans , Interleukin 1 Receptor Antagonist Protein/adverse effects , Interleukin 1 Receptor Antagonist Protein/pharmacology , Male , Middle Aged , Pandemics/prevention & control , Pandemics/statistics & numerical data , Prospective Studies , Receptors, Interleukin-1/therapeutic use , Statistics, Nonparametric
11.
Front Immunol ; 11: 575047, 2020.
Article in English | MEDLINE | ID: covidwho-895305

ABSTRACT

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. To test this hypothesis, heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n = 10) and COVID-19 patients (n = 48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity was associated with disease severity including the need for intensive care, lactate dehydrogenase levels, and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.


Subject(s)
Endothelium/pathology , Glucuronidase/antagonists & inhibitors , Glucuronidase/blood , Heparin Antagonists/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Tight Junctions/pathology , Aged , Betacoronavirus , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Creatinine/blood , Critical Care , Cross-Sectional Studies , Female , Glucuronidase/metabolism , Heparitin Sulfate/blood , Humans , Interleukin-6/blood , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , SARS-CoV-2
12.
Intensive Care Med ; 46(8): 1524-1535, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-615887

ABSTRACT

PURPOSE: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies. METHODS: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus. RESULTS: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung. CONCLUSION: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA.


Subject(s)
Aspergillus/isolation & purification , Betacoronavirus , Coronavirus Infections/complications , Influenza, Human/complications , Intensive Care Units , Pneumonia, Viral/complications , Pulmonary Aspergillosis , Antifungal Agents/therapeutic use , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/microbiology , COVID-19 , Galactose/analogs & derivatives , Humans , Mannans/analysis , Pandemics , Pulmonary Aspergillosis/diagnosis , Pulmonary Aspergillosis/etiology , Pulmonary Aspergillosis/prevention & control , SARS-CoV-2
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