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1.
Lancet Reg Health Am ; : 100228, 2022 Mar 23.
Article in English | MEDLINE | ID: covidwho-1757632

ABSTRACT

Background: Interleukin-6 inhibitors reduce mortality in severe COVID-19. British Columbia began using tocilizumab 8 mg/kg (maximum 800 mg) in January 2021 in critically ill patients with COVID-19, but due to drug shortages, decreased dosing to 400 mg IV fixed dose in April 2021. The aims of this study were twofold: to compare physiological responses and clinical outcomes of these two strategies, and examine the cost-effectiveness of treating all patients with 400 mg versus half the patients with 8 mg/kg and the other half without tocilizumab. Methods: This was a single-centre, before-after cohort study of critically ill COVID-19 patients treated with tocilizumab, and a control cohort treated with dexamethasone only. Physiological responses and clinical outcomes were compared between patients receiving both doses of tocilizumab and those receiving dexamethasone only. We built a decision tree model to examine cost-effectiveness. Findings: 152 patients were included; 40 received tocilizumab 8 mg/kg, 59 received 400 mg and 53 received dexamethasone only. Median CRP fell from 103 mg/L to 5.2 mg/L, 96 mg/L to 6.8 mg/L and from 81.3 mg/L to 48 mg/L in the 8 mg/kg, 400 mg tocilizumab, and dexamethasone only groups, respectively. 28-day mortality was 5% (n=2) vs 8% (n=5) vs 13% (n=7), with no significant difference in all pair-wise comparison. At an assumed willingness-to-pay threshold of $50,000 Canadian per life-year, utilizing 400 mg for all patients rather than 8 mg/kg for half the patients is cost-effective in 51.6% of 10,000 Monte Carlo simulations. Interpretation: Both doses of tocilizumab demonstrated comparable reduction of inflammation with similar 28-day mortality. Without consideration of equity, the net monetary benefits of providing 400 mg tocilizumab to all patients are comparable to 8 mg/kg to half the patients. In the context of ongoing drug shortages, fixed-dose 400 mg tocilizumab may be a practical, feasible and economical option. Funding: This work was supported by a gift donation from Hsu & Taylor Family to the VGH Foundation, and the Yale Bernard G. Forget Scholarship.

2.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327316

ABSTRACT

The COVID-19 pandemic continues to challenge the capacities of hospital ICUs which currently lack the ability to identify prospectively those patients who may require extended management. In this study of 90 ICU COVID-19 patients, we used multiplexed cytokine evaluation and, on 42 of these patients (binned into Initial and Replication Cohorts), CyTOF-based deep immunophenotyping. This revealed blood prognostic biomarkers that, at time of ICU admission, prospectively distinguish, with 91% sensitivity and 91% specificity, patients who will subsequently die or have long ICU stays (> 6 days) from those who will have short-stays (< 6 days). This is achieved through a tiered evaluation of serum IL-10 and targeted immunophenotyping of monocyte subsets (specifically, CD11clow classical monocytes) through statistical approaches. We have distilled this down to a prognostic test that could prove useful in guiding clinical resource allocation, treatment regimens and assessment of new therapeutic interventions.

3.
Med Microbiol Immunol ; 211(1): 37-48, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1626115

ABSTRACT

Mechanisms underlying the SARS-CoV-2-triggered hyperacute thrombo-inflammatory response that causes multi-organ damage in coronavirus disease 2019 (COVID-19) are poorly understood. Several lines of evidence implicate overactivation of complement. To delineate the involvement of complement in COVID-19, we prospectively studied 25 ICU-hospitalized patients for up to 21 days. Complement biomarkers in patient sera and healthy controls were quantified by enzyme-linked immunosorbent assays. Correlations with respiratory function and mortality were analyzed. Activation of complement via the classical/lectin pathways was variably increased. Strikingly, all patients had increased activation of the alternative pathway (AP) with elevated levels of activation fragments, Ba and Bb. This was associated with a reduction of the AP negative regulator, factor (F) H. Correspondingly, terminal pathway biomarkers of complement activation, C5a and sC5b-9, were significantly elevated in all COVID-19 patient sera. C5a and AP constituents Ba and Bb, were significantly associated with hypoxemia. Ba and FD at the time of ICU admission were strong independent predictors of mortality in the following 30 days. Levels of all complement activation markers were sustained throughout the patients' ICU stays, contrasting with the varying serum levels of IL-6, C-reactive protein, and ferritin. Severely ill COVID-19 patients have increased and persistent activation of complement, mediated strongly via the AP. Complement activation biomarkers may be valuable measures of severity of lung disease and the risk of mortality. Large-scale studies will reveal the relevance of these findings to thrombo-inflammation in acute and post-acute COVID-19.


Subject(s)
COVID-19 , Biomarkers , Complement Activation , Hospital Mortality , Humans , Hypoxia , SARS-CoV-2
4.
Front Immunol ; 12: 753558, 2021.
Article in English | MEDLINE | ID: covidwho-1463476

ABSTRACT

To date there is limited data on the immune profile and outcomes of solid organ transplant recipients who encounter COVID-19 infection early post-transplant. Here we present a unique case where the kidney recipient's transplant surgery coincided with a positive SARS-CoV-2 test and the patient subsequently developed symptomatic COVID-19 perioperatively. We performed comprehensive immunological monitoring of cellular, proteomic, and serological changes during the first 4 critical months post-infection. We showed that continuation of basiliximab induction and maintenance of triple immunosuppression did not significantly impair the host's ability to mount a robust immune response against symptomatic COVID-19 infection diagnosed within the first week post-transplant.


Subject(s)
Basiliximab/therapeutic use , COVID-19/immunology , Glomerulonephritis, IGA/therapy , Graft Rejection/immunology , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , SARS-CoV-2/physiology , Adult , Humans , Immune Tolerance , Immunity , Male , Perioperative Period , Transcriptome
6.
Cell Rep Med ; 2(5): 100269, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1199129

ABSTRACT

Data suggest that interleukin (IL)-6 blockade could reduce mortality in severe COVID-19, yet IL-6 is only modestly elevated in most patients. Chen et al. describe the role of soluble interleukin-6 receptor (sIL-6R) in IL-6 trans-signaling and how understanding the IL-6:sIL-6R axis might help define and treat COVID-19 cytokine storm syndrome.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/diagnosis , Receptors, Interleukin-6/analysis , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , COVID-19/complications , COVID-19/virology , Cytokine Release Syndrome/etiology , Humans , Interleukin-6/analysis , Interleukin-6/immunology , SARS-CoV-2/isolation & purification , Signal Transduction/drug effects
8.
Blood Rev ; 45: 100707, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064893

ABSTRACT

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.


Subject(s)
COVID-19/immunology , Castleman Disease/immunology , Cytokine Release Syndrome/immunology , Immunologic Factors/therapeutic use , Lymphohistiocytosis, Hemophagocytic/immunology , SARS-CoV-2/pathogenicity , Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal/therapeutic use , Biomarkers/blood , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Castleman Disease/drug therapy , Castleman Disease/pathology , Clinical Trials as Topic , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Ferritins/blood , Ferritins/immunology , Gene Expression Regulation , Humans , Immunotherapy, Adoptive/adverse effects , Interleukin-1/antagonists & inhibitors , Interleukin-1/blood , Interleukin-1/immunology , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Interleukin-6/immunology , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/pathology , Signal Transduction
9.
Alzheimer's & Dementia ; 16(S5):e047682, 2020.
Article in English | Wiley | ID: covidwho-959103

ABSTRACT

Abstract Background Multiple neurological manifestations of COVID-19 have been reported such as headache, anosmia, ischemic stroke, and cerebral hemorrhages. Objective characterization of the acute neurological damage in critically ill patients with COVID-19 has not yet been reported. Method We performed a prospective observational study of plasma brain biomarkers in critically ill patients with respiratory failure that were diagnosed with (COVID-19) or without (ICU control) COVID-19. Demographics, co-morbidities, daily clinical physiologic and laboratory data were collected. Plasma samples were drawn for measurement of neurofilament-light chain (NF-L), total tau (t-tau), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP). The primary neurological outcome was delirium as defined by the intensive care delirium screening checklist (ICDSC, scale 1 - 8). Associations between brain biomarkers and markers of respiratory failure of COVID-19 were analyzed. Result 27 patients with COVID-19 and 19 ICU controls were enrolled. The concentration of plasma GFAP, UCH-L1 and NF-L levels was higher in both groups compared to healthy controls. Compared to ICU controls, patients with COVID-19 had significantly higher GFAP (272 [150-555] pg/ml vs 118 [78.5-168] pg/ml, p=0.0009). In patients with COVID-19, GFAP (rho=0.5115, p=0.0064), UCH-L1 (rho=0.4056, p=0.0358) and NF-L (rho=0.6223, p=0.0005) were positively correlated with the ICDSC score and were higher in patients diagnosed with delirium (ICDSC ≥4) in the COVID-19 group but not ICU controls. There were no associations between PaO2/FiO2 or diagnosis of ARDS and plasma concentration of GFAP, t-tau, UCH-L1, or NF-L in patients with COVID-19. Conclusion Plasma GFAP is 2-fold higher in critically ill patients with COVID-19 compared to ICU controls, and higher concentrations of GFAP, UCH-L1 and NF-L are associated with delirium specifically in patients with COVID-19.

10.
CMAJ ; 192(47): E1550-E1558, 2020 Nov 23.
Article in French | MEDLINE | ID: covidwho-941710

ABSTRACT

CONTEXTE: La pandémie de maladie à coronavirus du syndrome respiratoire aigu sévère 2 (SRAS-CoV-2) est associée à une mortalité élevée dans les unités de soins intensifs (USI). Nous avons voulu décrire les caractéristiques cliniques et les issues des patients gravement atteints de la maladie à coronavirus 2019 (COVID-19) en contexte canadien. MÉTHODES: Nous avons procédé à l'étude rétrospective d'une série de cas graves d'infection au SRAS-CoV-2 confirmée en laboratoire hospitalisés dans l'une des 6 USI du Vancouver métropolitain, en Colombie-Britannique (Canada), entre le 21 février et le 14 avril 2020. Les données démographiques, les renseignements sur la prise en charge et les résultats ont été recueillis à partir des dossiers médicaux, électroniques ou non, des patients. RÉSULTATS: Entre le 21 février et le 14 avril 2020, 117 patients ont été admis dans une USI avec un diagnostic confirmé de COVID-19. L'âge médian était de 69 ans (écart interquartile [EI] 60­75 ans); et 38 (32,5 %) étaient des femmes. Au moins une comorbidité était présente chez 86 patients (73,5 %). La ventilation mécanique a été nécessaire chez 74 patients (63,2 %). La durée de la ventilation mécanique a été de 13,5 jours (EI 8­22 jours) dans l'ensemble et de 11 jours (II 6­16) chez les patients qui ont reçu leur congé de l'USI. Du tocilizumab a été administré à 4 patients et de l'hydroxychloroquine à 1 patient. En date du 5 mai 2020, 18 patients (15,4 %) étaient décédés, 12 (10,3 %) étaient toujours à l'USI, 16 (13,7 %) avaient obtenu leur congé de l'USI, mais restaient hospitalisés, et 71 (60,7 %) avaient pu retourner à la maison. INTERPRÉTATION: Dans cette étude, la mortalité chez les patients gravement malades de la COVID-19 hospitalisés dans une USI a été moins élevée que chez les patients d'études précédentes. Ces résultats donnent à penser que le pronostic des cas graves de COVID-19 pourrait ne pas être aussi sombre que ce qui avait d'abord été rapporté.


Subject(s)
COVID-19/therapy , Critical Care , Aged , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/mortality , COVID-19 Testing , Canada/epidemiology , Female , Hospitalization , Humans , Male , Middle Aged , Severity of Illness Index , Treatment Outcome
11.
Blood Adv ; 4(20): 4981-4989, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-873909

ABSTRACT

Studies on severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) suggest a protective effect of anti-A antibodies against viral cell entry that may hold relevance for SARS-CoV-2 infection. Therefore, we aimed to determine whether ABO blood groups are associated with different severities of COVID-19. We conducted a multicenter retrospective analysis and nested prospective observational substudy of critically ill patients with COVID-19. We collected data pertaining to age, sex, comorbidities, dates of symptom onset, hospital admission, intensive care unit (ICU) admission, mechanical ventilation, continuous renal replacement therapy (CRRT), standard laboratory parameters, and serum inflammatory cytokines. National (N = 398 671; P = .38) and provincial (n = 62 246; P = .60) ABO blood group distributions did not differ from our cohort (n = 95). A higher proportion of COVID-19 patients with blood group A or AB required mechanical ventilation (P = .02) and CRRT (P = .004) and had a longer ICU stay (P = .03) compared with patients with blood group O or B. Blood group A or AB also had an increased probability of requiring mechanical ventilation and CRRT after adjusting for age, sex, and presence of ≥1 comorbidity. Inflammatory cytokines did not differ between patients with blood group A or AB (n = 11) vs O or B (n = 14; P > .10 for all cytokines). Collectively, our data indicate that critically ill COVID-19 patients with blood group A or AB are at increased risk for requiring mechanical ventilation, CRRT, and prolonged ICU admission compared with patients with blood group O or B. Further work is needed to understand the underlying mechanisms.


Subject(s)
ABO Blood-Group System/blood , Betacoronavirus/isolation & purification , Coronavirus Infections/blood , Pneumonia, Viral/blood , Aged , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Critical Illness/epidemiology , Critical Illness/therapy , Cytokines/blood , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Prospective Studies , Respiration, Artificial , Retrospective Studies , Risk Factors , SARS-CoV-2 , Severity of Illness Index
12.
Crit Care Explor ; 2(10): e0238, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-873089

ABSTRACT

OBJECTIVES: To provide an objective characterization of acute neurologic injury in critically ill patients with coronavirus disease 2019. DESIGN: Prospective observational study. Demographics, comorbidities, and daily clinical physiologic and laboratory data were collected. Plasma levels of neurofilament-light chain, total tau, ubiquitin carboxy-terminal hydrolase L1, and glial fibrillary acidic protein were measured. The primary neurologic outcome was delirium defined by the Intensive Care Delirium Screening Checklist (scale 1-8). Associations among plasma biomarkers, respiratory failure, and inflammation were analyzed. SETTING: Multicenter study in ICUs. PATIENTS: Critically ill patients with respiratory failure, with coronavirus disease 2019, or without (ICU control). MEASUREMENTS AND MAIN RESULTS: A total of 27 patients with coronavirus disease 2019 and 19 ICU controls were enrolled. Compared with ICU controls with pneumonia of other etiology, patients with coronavirus disease 2019 had significantly higher glial fibrillary acidic protein (272 pg/mL [150-555 pg/mL] vs 118 pg/mL [78.5-168 pg/mL]; p = 0.0009). In coronavirus disease 2019 patients, glial fibrillary acidic protein (rho = 0.5115, p = 0.0064), ubiquitin carboxy-terminal hydrolase L1 (rho = 0.4056, p = 0.0358), and neurofilament-light chain (rho = 0.6223, p = 0.0005) positively correlated with Intensive Care Delirium Screening Checklist score and were increased in patients with delirium (Intensive Care Delirium Screening Checklist ≥ 4) in the coronavirus disease 2019 group but not in ICU controls. There were no associations between the measures of respiratory function or cytokines with glial fibrillary acidic protein, total tau, ubiquitin carboxy-terminal hydrolase L1, or neurofilament-light chain levels in patients with coronavirus disease 2019. CONCLUSIONS: Plasma glial fibrillary acidic protein is two-fold higher in critically ill patients with coronavirus disease 2019 compared with ICU controls. Higher levels of glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neurofilament-light chain associate with delirium in patients with coronavirus disease 2019. Elevated plasma glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neurofilament-light chain are independent of respiratory function and peripheral cytokines.

13.
Crit Care Explor ; 2(9): e0203, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-873077

ABSTRACT

OBJECTIVES: The majority of coronavirus disease 2019 mortality and morbidity is attributable to respiratory failure from severe acute respiratory syndrome coronavirus 2 infection. The pathogenesis underpinning coronavirus disease 2019-induced respiratory failure may be attributable to a dysregulated host immune response. Our objective was to investigate the pathophysiological relationship between proinflammatory cytokines and respiratory failure in severe coronavirus disease 2019. DESIGN: Multicenter prospective observational study. SETTING: ICU. PATIENTS: Critically ill patients with coronavirus disease 2019 and noncoronavirus disease 2019 critically ill patients with respiratory failure (ICU control group). INTERVENTIONS: Daily measurement of serum inflammatory cytokines. MEASUREMENTS AND MAIN RESULTS: Demographics, comorbidities, clinical, physiologic, and laboratory data were collected daily. Daily serum samples were drawn for measurements of interleukin-1ß, interleukin-6, interleukin-10, and tumor necrosis factor-α. Pulmonary outcomes were the ratio of Pao2/Fio2 and static lung compliance. Twenty-six patients with coronavirus disease 2019 and 22 ICU controls were enrolled. Of the patients with coronavirus disease 2019, 58% developed acute respiratory distress syndrome, 62% required mechanical ventilation, 12% underwent extracorporeal membrane oxygenation, and 23% died. A negative correlation between interleukin-6 and Pao2/Fio2 (rho, -0.531; p = 0.0052) and static lung compliance (rho, -0.579; p = 0.033) was found selectively in the coronavirus disease 2019 group. Diagnosis of acute respiratory distress syndrome was associated with significantly elevated serum interleukin-6 and interleukin-1ß on the day of diagnosis. CONCLUSIONS: The inverse relationship between serum interleukin-6 and Pao2/Fio2 and static lung compliance is specific to severe acute respiratory syndrome coronavirus 2 infection in critically ill patients with respiratory failure. Similar observations were not found with interleukin-ß or tumor necrosis factor-α.

16.
CMAJ ; 192(26): E694-E701, 2020 06 29.
Article in English | MEDLINE | ID: covidwho-430160

ABSTRACT

BACKGROUND: Pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with high intensive care unit (ICU) mortality. We aimed to describe the clinical characteristics and outcomes of critically ill patients with coronavirus disease 2019 (COVID-19) in a Canadian setting. METHODS: We conducted a retrospective case series of critically ill patients with laboratory-confirmed SARS-CoV-2 infection consecutively admitted to 1 of 6 ICUs in Metro Vancouver, British Columbia, Canada, between Feb. 21 and Apr. 14, 2020. Demographic, management and outcome data were collected by review of patient charts and electronic medical records. RESULTS: Between Feb. 21 and Apr. 14, 2020, 117 patients were admitted to the ICU with a confirmed diagnosis of COVID-19. The median age was 69 (interquartile range [IQR] 60-75) years, and 38 (32.5%) were female. At least 1 comorbidity was present in 86 (73.5%) patients. Invasive mechanical ventilation was required in 74 (63.2%) patients. The duration of mechanical ventilation was 13.5 (IQR 8-22) days overall and 11 (IQR 6-16) days for patients successfully discharged from the ICU. Tocilizumab was administered to 4 patients and hydroxychloroquine to 1 patient. As of May 5, 2020, a total of 18 (15.4%) patients had died, 12 (10.3%) remained in the ICU, 16 (13.7%) were discharged from the ICU but remained in hospital, and 71 (60.7%) were discharged home. INTERPRETATION: In our setting, mortality in critically ill patients with COVID-19 admitted to the ICU was lower than in previously published studies. These data suggest that the prognosis associated with critical illness due to COVID-19 may not be as poor as previously reported.


Subject(s)
Coronavirus Infections/therapy , Critical Care , Pneumonia, Viral/therapy , Aged , Betacoronavirus , British Columbia/epidemiology , COVID-19 , Coronavirus Infections/mortality , Female , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
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