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Event: 1868

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Hyperinflammation

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Hyperinflammation
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
chronic inflammatory response increased
regulation of chronic inflammatory response increased
interleukin-6 production interleukin-6 increased
interleukin-1 beta production interleukin-1 beta increased
tumor necrosis factor secretion tumor necrosis factor alpha increased
Increased inflammatory response increased
Increased serum ferritin Ferritin increased
lactate dehydrogenase activity increased
Elevated C-reactive protein level C-reactive protein increased
Lymphopenia lymphocyte decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Dysregulated fibrinolysis/bradykinin leading to hyperinflammation AdverseOutcome Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development
SARS-CoV2 to hyperinflammation AdverseOutcome Arthur Author (send email) Under development: Not open for comment. Do not cite
TLR9 activation leading to Multi Organ Failure and ARDS KeyEvent Cataia Ives (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
humans Homo sapiens High NCBI
mouse Mus musculus Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Mixed

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Hyperinflammation can be defined as an uncontrolled and self-perpetuating inflammatory process that results in tissue damage. The state of hyperinflammation is also observed in cytokine storm syndrome, cytokine release syndrome, haemophagocytic lymphohistiocytosis, macrophage activation syndrome and in conditions of sepsis; however, it is not a frequent observation. For example, in COVID-19 infection, hyperinflammation plays a critical role in driving the disease severity. Although high viral titre initiates the cascade, the disease severity itself is dependent on the severity of the inflammatory state.

Clinically, the hallmarks of hyperinflammation state include excessive serum levels of pro-inflammatory mediator C-reactive protein (CRP), reduced or absence of lymphocytes (lymphopenia), high levels of ferritin and D-dimer, and increased lactate dehydrogenase. Higher neutrophil to lymphocyte ratio is another clinical marker. Some research studies have also associated high serum levels of IL6 protein and accumulation of neutrophils to be causal and indicative of hyperinflammation. Other molecular markers associated with hyperinflammation include IL1ꞵ and TNFɑ and have together with IL6 and a multitude of other cytokines, chemokines and other proinflammatory factors been identified as potential therapeutic targets (Desvaux et al. 2021). While the total serum levels of these markers is important, more critically, how fast the levels increase in serum is taken into consideration in judging the severity (Bergamaschi et al. 2021). The number of studies that have reported on the various markers of hyperinflammation is listed in Table-1.

Although the initiation and promotion of inflammation involves several cell types including epithelial cells, alveolar macrophages, type I and II pneumocytes and dendritic cells, the cell types that play role on inducing hyperinflammatory state may include macrophages, dendritic cells and neutrophils. Lack of neutrophil plays an important role in slowing the viral clearance and thus perpetuating the condition. Hyperferritinaemia is associated with high macrophage activation.

Weight of evidence

KE Hyperinflammation

References

Markers

Comments

Research

Clinical

Clinical

Clinical

Clinical

Research

IL6, TNFa

CRP

Lymphopenia

Ferritin

Lactate dehydrogenase

Impaired IFN 1 type response

Human

Lazear H.M et al., Immunity. 2019;50:907–923. 

Increased protein levels, NFkB pathway activation

Reduced IFN stimulated genes

Human

Zhang B, Zhou X, Qiu Y, et al. Clinical characteristics of 82 death cases with COVID19. medRxiv. 2020.

Increased

Increased

Present, also thrombocytopenia

IncreasedIncreased D-dimer

Increased

Human

J Clin.  Invest. 2020;130(5):2620-2629. https://doi.org/10.1172/JCI137244

Increased

Increased

Present

Increased D-dimer

Increased

Human

Hadjadj et al., Science doi: 10.1126/science.abc6027

Increasedprotein

Impaired

Human

Del Valle DM et al., Medrxiv : the Preprint Server for Health Sciences. 2020 May. 

Increased protein

Impaired

Human

Chen G ei al., J Clin Invest. 2020;130(5):2620-2629

Increased IL-6

Present

Increased ferritin and D-dimer

Increased

Marginal reduction

Human

Cheng L et al.,

Journal of Clinical Laboratory Analysis Volume34, Issue10

October 2020 e23618

https://doi.org/10.1002/jcla.23618

IL-6 increased

Increased ferritin levels

Review – meta analysis of 52 studies that have data for ferritin levels. Showing severity can be predicted by ferritin levels. Connections with inflammation state.

Human

Manson JJ et al., The Lancet Rheumatology

Volume 2, Issue 10, October 2020, Pages e594-e602

Increased

Increased Ferritin levels

Logitudinal cohort study showing association of hyperinflammation with prognosis. Only CRP and Ferritin levels considered.

Human

Caricchio R, et al.,  Ann Rheum Dis doi:10.1136/ annrheumdis-2020-218323

Increased

Increased

Increased

Recommended criteria for assessing hyperinflammation

Human

Mojtabavi, H., et al., Eur Cytokine Netw 31, 44–49 (2020). https://doi.org/10.1684/ecn.2020.0448

Increased

Review- meta-analysis of available data. 11 studies included.

Human

Henry B et al.,  Acta Biomed. 2020;91(3):e2020008. doi:10.23750/abm.v91i3.10217

Lymphopenia and neutrophilia

Meta-analysis study –

22 studies included. Correlation between lymphopenia and neutrophilia at admission with severity of disease.

Human

Jin J-M et al., Front. Public Health, 29 April 2020 | https://doi.org/10.3389/fpubh.2020.00152

Gender differences

Ex vivo, human lung tissue

Chu H, et al., Clin Infect Dis. 2020;71(6):1400-1409.

Increased IL-6

Impaired IFN I, II, III signalling

Mouse

Channappanavar et al.,  Cell Host Microbe 19 (2) (2016) 181–193,

Reduced IFN I response

SARS-COV

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Hyperinflammation is observed in all age groups with high rates of infection and mortality observed in aged population. In children, although the rate of infection is low, hyperinflammatory syndrome is observed leading to long term disabilities. However, mortality rate in young children and adults below 40 years of age is less pronounced. Data in other developmental stages is lacking.

Prevalence of hyperinflammation is same in men and women; however, studies have found that men develop more severe symptoms than women.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

References

List of the literature that was cited for this KE description. More help

1. Caricchio R, et al.,  Ann Rheum Dis doi:10.1136/ annrheumdis-2020-218323

2. Channappanavar et al.,  Cell Host Microbe 19 (2) (2016) 181–193,

3. Chen G ei al., J Clin Invest. 2020;130(5):2620-2629

4. Cheng L et al.,Journal of Clinical Laboratory Analysis Volume34, Issue10, October 2020 e23618, https://doi.org/10.1002/jcla.23618

5. Chu H, et al., Clin Infect Dis. 2020;71(6):1400-1409.

6. Del Valle DM et al., Medrxiv : the Preprint Server for Health Sciences. 2020 May.

7. J Clin.  Invest. 2020;130(5):2620-2629. https://doi.org/10.1172/JCI137244

8. Jin J-M et al., Front. Public Health, 29 April 2020 | https://doi.org/10.3389/fpubh.2020.00152

9. Hadjadj et al., Science doi: 10.1126/science.abc6027

10. Henry B et al.,  Acta Biomed. 2020;91(3):e2020008. doi:10.23750/abm.v91i3.10217

11. Lazear H.M et al., Immunity. 2019;50:907–923.

12. Manson JJ et al., The Lancet Rheumatology Volume 2, Issue 10, October 2020, Pages e594-e602

13. Mojtabavi, H., et al., Eur Cytokine Netw 31, 44–49 (2020). https://doi.org/10.1684/ecn.2020.0448

14. Zhang B, Zhou X, Qiu Y, et al. Clinical characteristics of 82 death cases with COVID‐19. medRxiv. 2020.