Hyperinflammation

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

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.

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