This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2019. Other selected articles can be found online at ...https://www.biomedcentral.com/collections/annualupdate2019 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .
Access to critical care is a crucial component of healthcare systems. In low-income countries, the burden of critical illness is substantial, but the capacity to provide care for critically ill ...patients in intensive care units (ICUs) is unknown. Our aim was to systematically review the published literature to estimate the current ICU capacity in low-income countries.
We searched 11 databases and included studies of any design, published 2004-August 2014, with data on ICU capacity for pediatric and adult patients in 36 low-income countries (as defined by World Bank criteria; population 850 million). Neonatal, temporary, and military ICUs were excluded. We extracted data on ICU bed numbers, capacity for mechanical ventilation, and information about the hospital, including referral population size, public accessibility, and the source of funding. Analyses were descriptive.
Of 1,759 citations, 43 studies from 15 low-income countries met inclusion criteria. They described 36 individual ICUs in 31 cities, of which 16 had population greater than 500,000, and 14 were capital cities. The median annual ICU admission rate was 401 (IQR 234-711; 24 ICUs with data) and median ICU size was 8 beds (IQR 5-10; 32 ICUs with data). The mean ratio of adult and pediatric ICU beds to hospital beds was 1.5% (SD 0.9%; 15 hospitals with data). Nepal and Uganda, the only countries with national ICU bed data, had 16.7 and 1.0 ICU beds per million population, respectively. National data from other countries were not available.
Low-income countries lack ICU beds, and more than 50% of these countries lack any published data on ICU capacity. Most ICUs in low-income countries are located in large referral hospitals in cities. A central database of ICU resources is required to evaluate health system performance, both within and between countries, and may help to develop related health policy.
Mortality caused by septic shock may be determined by a systemic inflammatory response, independent of the inciting infection, but it may also be influenced by the anatomic source of infection.
To ...determine the association between the anatomic source of infection and hospital mortality in critically ill patients who have septic shock.
This was a retrospective, multicenter cohort study of 7,974 patients who had septic shock in 29 academic and community intensive care units in Canada, the United States, and Saudi Arabia from January 1989 to May 2008.
Subjects were assigned 1 of 20 anatomic sources of infection based on clinical diagnosis and/or isolation of pathogens. The primary outcome was hospital mortality. Overall crude hospital mortality was 52% (21-85% across sources of infection). Variation in mortality remained after adjusting for year of admission, geographic source of admission, age, sex, comorbidities, community- versus hospital-acquired infection, and organism type. The source of infection with the highest standardized hospital mortality was ischemic bowel (75%); the lowest was obstructive uropathy-associated urinary tract infection (26%). Residual variation in adjusted hospital mortality was not explained by Acute Physiology and Chronic Health Evaluation II score, number of Day 1 organ failures, bacteremia, appropriateness of empiric antimicrobials, or adjunct therapies. In patients who received appropriate antimicrobials after onset of hypotension, source of infection was associated with death after adjustment for both predisposing and downstream factors.
Anatomic source of infection should be considered in future trial designs and analyses, and in development of prognostic scoring systems.
Identifying febrile children at risk of sepsis in low-resource settings can improve survival, but recognition triage tools are lacking. Here we test the hypothesis that measuring circulating markers ...of immune and endothelial activation may identify children with sepsis at risk of all-cause mortality. In a prospective cohort study of 2,502 children in Uganda, we show that Soluble Triggering Receptor Expressed on Myeloid cells-1 (sTREM-1) measured at first clinical presentation, had high predictive accuracy for subsequent in-hospital mortality. sTREM-1 had the best performance, versus 10 other markers, with an AUROC for discriminating children at risk of death of 0.893 in derivation (95% CI 0.843-0.944) and 0.901 in validation (95% CI 0.856-0.947) cohort. sTREM-1 cutoffs corresponding to a negative likelihood ratio (LR) of 0.10 and a positive LR of 10 classified children into low (1,306 children, 53.1%), intermediate (942, 38.3%) and high (212, 8.6%) risk zones. The estimated incidence of death was 0.5%, 3.9%, and 31.8%, respectively, suggesting sTREM-1 could be used to risk-stratify febrile children. These findings do not attempt to derive a risk prediction model, but rather define sTREM-1 cutoffs as the basis for rapid triage test for all cause fever syndromes in children in low-resource settings.
Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals
, many others experience milder symptoms. Here, to gain a ...more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)
across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.
Sepsis, a dysregulated host response to infection that causes life-threatening organ dysfunction, is a highly heterogeneous syndrome with no specific treatment. Although sepsis can be caused by a ...wide variety of pathogenic organisms, endothelial dysfunction leading to vascular leak is a common mechanism of injury that contributes to the morbidity and mortality associated with the syndrome. Perturbations to the angiopoietin (Ang)/Tie2 axis cause endothelial cell activation and contribute to the pathogenesis of sepsis. In this review, we summarize how the Ang/Tie2 pathway is implicated in sepsis and describe its prognostic as well as therapeutic utility in life-threatening infections.
The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of ...comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.
Biomarkers can prognosticate outcome and enable risk-stratification. In severe infection, focusing on multiple markers reflecting pathophysiological mechanisms of organ injury could enhance ...management and pathway-directed therapeutics. Limited data exist on the performance of multiplex biomarker platforms. Our goal was to compare endothelial and immune activation biomarkers in severe pediatric infections using two multiplex platforms. Frozen plasma from 410 children presenting to the Jinja Regional Hospital in Uganda with suspected infection was used to measure biomarkers of endothelial (Angiopoietin-2, sFlt-1, sVCAM-1, sICAM-1) and immune (IL-6, IP-10, sTNFR-1, CHI3L1) activation. Two multiplex platforms (Luminex®, EllaTM) based on monoclonal antibody sandwich immunoassays using biotin-streptavidin conjugate chemistry were selected with reagents from R&D Systems. The two platforms differed in ease and time of completion, number of samples per assay, and dynamic concentration range. Intra-assay variability assessed using a coefficient of variation (CV%) was 2.2-3.4 for Luminex® and 1.2-2.9 for EllaTM. Correlations for biomarker concentrations within dynamic range of both platforms were best for IL-6 (ρ = 0.96, p<0.0001), IP-10 (ρ = 0.94, p<0.0001) and sFlt-1 (ρ = 0.94, p<0.0001). Agreement between concentrations obtained by both methods assessed by the Bland-Altman test varied, with best agreement for CHI3L1. Our data suggest that biomarkers of endothelial and immune activation can be readily measured with multiplex platforms. Luminex® and EllaTM produced reliable results with excellent CV% values. The EllaTM platform was more automated and completed in 75 minutes, potentially compatible with near-patient use. Trends in concentrations obtained by these methods were highly correlated, although absolute values varied, suggesting caution is required when comparing data from different multiplex platforms.
BACKGROUNDWhether airspace biomarkers add value to plasma biomarkers in studying acute respiratory distress syndrome (ARDS) is not well understood. Mesenchymal stromal cells (MSCs) are an ...investigational therapy for ARDS, and airspace biomarkers may provide mechanistic evidence for MSCs' impact in patients with ARDS.METHODSWe carried out a nested cohort study within a phase 2a safety trial of treatment with allogeneic MSCs for moderate-to-severe ARDS. Nonbronchoscopic bronchoalveolar lavage and plasma samples were collected 48 hours after study drug infusion. Airspace and plasma biomarker concentrations were compared between the MSC (n = 17) and placebo (n = 10) treatment arms, and correlation between the two compartments was tested. Airspace biomarkers were also tested for associations with clinical and radiographic outcomes.RESULTSCompared with placebo, MSC treatment significantly reduced airspace total protein, angiopoietin-2 (Ang-2), IL-6, and soluble TNF receptor-1 concentrations. Plasma biomarkers did not differ between groups. Each 10-fold increase in airspace Ang-2 was independently associated with 6.7 fewer days alive and free of mechanical ventilation (95% CI, -12.3 to -1.0, P = 0.023), and each 10-fold increase in airspace receptor for advanced glycation end-products (RAGE) was independently associated with a 6.6-point increase in day 3 radiographic assessment of lung edema score (95% CI, 2.4 to 10.8, P = 0.004).CONCLUSIONMSCs reduced biological evidence of lung injury in patients with ARDS. Biomarkers from the airspaces provide additional value for studying pathogenesis, treatment effects, and outcomes in ARDS.TRIAL REGISTRATIONClinicalTrials.gov NCT02097641.FUNDINGNational Heart, Lung, and Blood Institute.
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