Critical Illness–Induced Immune Suppression: Current State of the Science

Critical illness comprises a heterogeneous group of serious medical conditions that typically involve an initial proinflammatory process. A compensatory anti-inflammatory response may occur that, if severe and persistent, places the patient at high risk for adverse outcomes including secondary infection and death. Monitoring strategies can identify these patients through measurement of innate and adaptive immune function. Reductions in monocyte HLA-DR expression, reduced cytokine production capacity, increased inhibitory cell surface molecule expression, and lymphopenia have all been associated with this immune-suppressed state. Intriguing data suggest that critical illness–induced immune suppression may be reversible with agents such as interferon-γ, granulocyte macrophage colony-stimulating factor, interleukin 7, or anti–programmed death-1 therapy. Future approaches for characterization of patient-specific immune derangements and individualized treatment could revolutionize how we recognize and prevent complications in critically ill patients.

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Adaptive metabolic and inflammatory responses identified using accelerated aging metrics are linked to adverse outcomes in severe SARS-CoV-2 infection

The Journals of Gerontology Series A ◽

10.1093/gerona/glab078 ◽

2021 ◽

Author(s):

Alejandro Márquez-Salinas ◽

Carlos A Fermín-Martínez ◽

Neftalí Eduardo Antonio-Villa ◽

Arsenio Vargas-Vázquez ◽

Enrique C. Guerra ◽

...

Keyword(s):

Critical Illness ◽

Proportional Hazards ◽

Inflammatory Responses ◽

Age Groups ◽

Accelerated Aging ◽

Cox Proportional Hazards ◽

Adverse Outcomes ◽

Adaptive Responses ◽

Predictive Capacity ◽

Risk Of Death

Abstract Background Chronological age (CA) is a predictor of adverse COVID-19 outcomes; however, CA alone does not capture individual responses to SARS-CoV-2 infection. Here, we evaluated the influence of aging metrics PhenoAge and PhenoAgeAccel to predict adverse COVID-19 outcomes. Furthermore, we sought to model adaptive metabolic and inflammatory responses to severe SARS-CoV-2 infection using individual PhenoAge components. Methods In this retrospective cohort study, we assessed cases admitted to a COVID-19 reference center in Mexico City. PhenoAge and PhenoAgeAccel were estimated using laboratory values at admission. Cox proportional hazards models were fitted to estimate risk for COVID-19 lethality and adverse outcomes (ICU admission, intubation, or death). To explore reproducible patterns which model adaptive responses to SARS-CoV-2 infection, we used k-means clustering using PhenoAge components. Results We included 1068 subjects of whom 222 presented critical illness and 218 died. PhenoAge was a better predictor of adverse outcomes and lethality compared to CA and SpO2 and its predictive capacity was sustained for all age groups. Patients with responses associated to PhenoAgeAccel>0 had higher risk of death and critical illness compared to those with lower values (log-rank p<0.001). Using unsupervised clustering we identified four adaptive responses to SARS-CoV-2 infection: 1) Inflammaging associated with CA, 2) metabolic dysfunction associated with cardio-metabolic comorbidities, 3) unfavorable hematological response, and 4) response associated with favorable outcomes. Conclusions Adaptive responses related to accelerated aging metrics are linked to adverse COVID-19 outcomes and have unique and distinguishable features. PhenoAge is a better predictor of adverse outcomes compared to CA.

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Association Between Room Location and Adverse Outcomes in Hospitalized Patients

HERD Health Environments Research & Design Journal ◽

10.1177/1937586718806702 ◽

2018 ◽

Vol 12 (2) ◽

pp. 21-29 ◽

Cited By ~ 1

Author(s):

Anoop Mayampurath ◽

Christopher Ward ◽

John Fahrenbach ◽

Cynthia LaFond ◽

Michael Howell ◽

...

Keyword(s):

Critical Illness ◽

Severity Of Illness ◽

Adverse Outcomes ◽

Sensitivity Analyses ◽

Additional Risk Factor ◽

Inhospital Mortality ◽

Additional Risk ◽

Increased Risk ◽

Euclidean Distances ◽

Time Of Admission

Objective: To investigate whether a patient’s proximity to the nurse’s station or ward entrance at time of admission was associated with increased risk of adverse outcomes. Method: We conducted a retrospective cohort study of consecutive adult inpatients to 13 medical–surgical wards at an academic hospital from 2009 to 2013. Proximity of admission room to the nurse’s station and to the ward entrance was measured using Euclidean distances. Outcomes of interest include development of critical illness (defined as cardiac arrests or transfer to an intensive care unit), inhospital mortality, and increase in length of stay (LOS). Results: Of the 83,635 admissions, 4,129 developed critical illness and 1,316 died. The median LOS was 3 days. After adjusting for admission severity of illness, ward, shift, and year, we found no relationship between proximity at admission to nurse’s station our outcomes. However, patients admitted to end of the ward had higher risk of developing critical illness (odds ratio [ OR] = 1.15, 95% confidence interval [CI] = [1.08, 1.23]), mortality ( OR = 1.16, 95% CI [1.03, 1.33]), and a higher LOS (13-hr increase, 95% CI [10, 15] hours) compared to patients admitted closer to the ward entrance. Similar results were observed in sensitivity analyses adjusting for isolation room patients and considering patients without room transfers in the first 48 hr. Conclusions: Our study suggests that being away from the nurse’s station did not increase the risk of these adverse events in ward patients, but being farther from the ward entrance was associated with increase in risk of adverse outcomes. Patient safety can be improved by recognizing this additional risk factor.

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Coordinated acquisition of inhibitory and activating receptors and functional properties by developing human natural killer cells

Blood ◽

10.1182/blood-2006-04-020198 ◽

2006 ◽

Vol 108 (12) ◽

pp. 3824-3833 ◽

Cited By ~ 107

Author(s):

Bartosz Grzywacz ◽

Nandini Kataria ◽

Magdalena Sikora ◽

Robert A. Oostendorp ◽

Elaine A. Dzierzak ◽

...

Keyword(s):

Cell Differentiation ◽

Natural Killer ◽

Cell Line ◽

Nk Cell ◽

Fetal Liver ◽

Interferon Γ ◽

Intermediate Phenotype ◽

Interleukin 7 ◽

Nk Cell Differentiation ◽

And Function

AbstractThe stages of human natural killer (NK) cell differentiation are not well established. Culturing CD34+ progenitors with interleukin 7 (IL-7), IL-15, stem cell factor (SCF), FLT-3L, and murine fetal liver cell line (EL08.1D2), we identified 2 nonoverlapping subsets of differentiating CD56+ cells based on CD117 and CD94 (CD117highCD94– and CD117low/–CD94+ cells). Both populations expressed CD161 and NKp44, but differed with respect to NKp30, NKp46, NKG2A, NKG2C, NKG2D, CD8, CD16, and KIR. Only the CD117low/– CD94+ population displayed cytotoxicity and interferon-γ production. Both populations arose from a single CD34+CD38– Lin– cell and their percentages changed over time in a reciprocal fashion, with CD117highCD94– cells predominating early and decreasing due to an increase of the CD117low/–CD94+ population. These 2 subsets represent distinct stages of NKcell differentiation, since purified CD117high CD94– cells give rise to CD117low/–CD94+ cells. The stromal cell line (EL08.1D2) facilitated the transition from CD117highCD94– to CD117low/–CD94+ via an intermediate phenotype (CD117lowCD94low/–). EL08.1D2 also maintained the mature phenotype, preventing the reversion of CD117low/–CD94+ cells to the intermediate (CD117lowCD94low/–) phenotype. An analogous population of CD56+CD117highCD94– cells was found in cord blood. The identified stages of NK-cell differentiation provide evidence for coordinated acquisition of HLA-specific inhibitory receptors (ie, CD94/NKG2A) and function in developing human NK cells.

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Critical Illness Stress-induced Immune Suppression

Yearbook of Intensive Care and Emergency Medicine - Intensive Care Medicine ◽

10.1007/978-3-540-49433-1_20 ◽

2007 ◽

pp. 217-228 ◽

Cited By ~ 2

Author(s):

J. A. Carcillo

Keyword(s):

Critical Illness ◽

Immune Suppression

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Caring for Older Adults During and After Critical Illness

10.1093/oso/9780190077013.003.0010 ◽

2021 ◽

pp. 216-234

Author(s):

Maria C. Duggan ◽

Julie Van ◽

E. Wesley Ely

Keyword(s):

Older Adults ◽

Critical Illness ◽

Health Care Professionals ◽

Interdisciplinary Approach ◽

Adverse Outcomes ◽

Evidence Based ◽

Complex Population ◽

Multiple Domains ◽

Over Time

Over half of people with critical illness are older adults, and the number of older adults admitted to intensive care units has been increasing over time. Older adults have increased vulnerability to disease, disability, and adverse outcomes across many domains. To address this most effectively, a unique, interdisciplinary approach is necessary to optimize not only survival but also functional status and quality of life. A shortage of health care professionals equipped to care for the aging population makes it imperative that all professionals become aware of basic principles of caring for older adults. To equip them to care for this complex population, this chapter provides an overview of how aging impacts multiple domains of an older person with critical illness and describes evidence-based approaches to caring for older adults with critical illness.

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Nutrition and malnutrition in elderly patients

Italian Journal of Medicine ◽

10.4081/itjm.2010.99 ◽

2013 ◽

pp. 99-104

Author(s):

Daniela Tozzuoli ◽

Emanuele Ceccherini ◽

Claudio Pedace

Keyword(s):

Elderly Patients ◽

Nutritional Support ◽

Adverse Outcomes ◽

Patient Specific ◽

Artificial Nutrition ◽

Oral Supplementation ◽

Protein Energy ◽

Age Related ◽

Clinical Conditions ◽

Underlying Diseases

Protein-energy undernutrition is a very common problem among elderly patients. It is promoted by age-related decreases in the basal metabolic rate, physiological change in body composition, progressive dysphagia, physical and/or cognitive impairments, depression, socioeconomic factors, effects of drugs on absorption and utilization of nutrients, and other factors. Several studies suggest that nutritional support can lower the risk of adverse outcomes among undernourished elderly patients. Monitoring food intake in patients with dysphagia may be useful in deciding between oral supplementation or artificial nutrition. The decision to provide nutritional support and the route to be used will depend on the clinical conditions of the patient, the severity of the dysphagia, the expected course of any underlying diseases, and several other patient-specific considerations. In geriatric patients, the main objectives of this type of therapy are usually the maintenance of function and improvement of the quality of life.

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Cancer immunotherapy and toxic epidermal necrolysis

BMJ Supportive & Palliative Care ◽

10.1136/bmjspcare-2019-002135 ◽

2020 ◽

Vol 10 (3) ◽

pp. 314-315 ◽

Cited By ~ 1

Author(s):

Liyan Zhang ◽

Lin Shen ◽

Yuhan Lu ◽

Jing Xue

Keyword(s):

Toxic Epidermal Necrolysis ◽

Secondary Infection ◽

Young Female ◽

Multiple Organ ◽

Adverse Outcomes ◽

Nutrition Support ◽

Systemic Glucocorticoid ◽

Ensure Patient Safety ◽

Mucous Membranes ◽

Comprehensive Treatments

ObjectivesImmunotherapy has come to play an increasingly important role in cancer treatment. Accordingly, immune-related adverse events (irAEs) have drawn considerable attention. In this case, a young female patient developed immune-related toxic epidermal necrolysis (TEN). The same irAEs have been rarely reported in previous studies. In this study, we describe the treatment and care methods used in this case in detail in order to provide a reference for clinical practice.MethodsAfter being diagnosed with TEN, the patient accepted systemic glucocorticoid therapy, timely care of skin and mucous membranes, nutrition support, antiacid therapy, anti-inflammatory, analgesics and other supportive measures.ResultsThe patient’s skin recovered completely, and no serious adverse outcomes, such as secondary infection or multiple organ failure, occurred during treatment.ConclusionMedical staff should be able to identify the performance of rare irAEs such as TENs and actively explore comprehensive treatments to ensure patient safety and avoid adverse outcomes.

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P140: Risk factors for adverse outcomes in hyperglycemic patients presenting to the emergency department: a systematic review

CJEM ◽

10.1017/cem.2018.338 ◽

2018 ◽

Vol 20 (S1) ◽

pp. S106-S107

Author(s):

L. Siddiqi ◽

K. Van Aarsen ◽

A. Iansavitchene ◽

J. W. Yan

Keyword(s):

Systematic Review ◽

Protective Factors ◽

Quality Assessment ◽

Research Question ◽

Age Groups ◽

Adverse Outcomes ◽

Assessment Scale ◽

Patient Specific ◽

Diabetic Patients ◽

The Past

Introduction: Hyperglycemia is a significant cause of morbidity and mortality, often resulting in adverse outcomes such as recurrent ED visits, hospitalization or death. The objective of this study was to perform a systematic review to identify predictors of these adverse outcomes among patients who present to the ED with hyperglycemia. Methods: Electronic searches of Medline and EMBASE were conducted for studies published in English between the years 1946 and June 2017. Studies with patients presenting to the ED with hyperglycemia were eligible for inclusion. Both adult and pediatric populations were included, as were diabetic and non-diabetic patients. Two reviewers independently screened all titles and abstracts for relevance to the research question. If consensus could not be reached, full-length manuscripts were reviewed. For any discrepancy, a third reviewer was consulted, and disagreement was resolved through discussion. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Study- and patient-specific data were then extracted and presented descriptively in the systematic review. Results: Thirteen observational studies were included, with a combined total of 664,829 patients. The studies scored between 5 to 8 on the Quality Assessment Scale out of a possible total of 8. Predictors of adverse outcomes included patients in both older and younger (< 25) age groups, history of diabetes, multiple comorbidities, patients requiring insulin, sepsis and hyperlactatemia, access to a family physician, a sentinel hyperglycemia visit in the past month, and triage glucose level > 20 mmol/L. Protective factors included no admissions in the past year, care from a diabetes team while in hospital, systolic blood pressure between 90-150 mmHg and heart rate > 110 bpm. Conclusion: This systematic review found eight predictors and four protective factors for adverse outcomes in patients presenting to the ED with hyperglycemia. These factors should be considered for easier identification of higher-risk patients for adverse outcomes in order to guide management and follow-up.

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Immune Immunomodulation in Coronavirus Disease 2019 (COVID-19): Strategic Considerations for Personalized Therapeutic Intervention

Clinical Infectious Diseases ◽

10.1093/cid/ciaa904 ◽

2020 ◽

Cited By ~ 3

Author(s):

Mark W Hall ◽

Ila Joshi ◽

Luis Leal ◽

Eng Eong Ooi

Keyword(s):

Immune Response ◽

Critical Illness ◽

Severe Acute Respiratory Syndrome ◽

Systemic Inflammation ◽

Host Defense ◽

Shortest Path ◽

Immune Suppression ◽

Host Response ◽

Repair Mechanisms ◽

Anticytokine Therapy

Abstract We are learning that the host response to severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2) infection is complex and highly dynamic. Effective initial host defense in the lung is associated with mild symptoms and disease resolution. Viral evasion of the immune response can lead to refractory alveolar damage, ineffective lung repair mechanisms, and systemic inflammation with associated organ dysfunction. The immune response in these patients is highly variable and can include moderate to severe systemic inflammation and/or marked systemic immune suppression. There is unlikely to be a “one size fits all” approach to immunomodulation in patients with coronavirus disease 2019 (COVID-19). We believe that a personalized, immunophenotype-driven approach to immunomodulation that may include anticytokine therapy in carefully selected patients and immunostimulatory therapies in others is the shortest path to success in the study and treatment of patients with critical illness due to COVID-19.

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