The following are portions of an outstanding 2012 article on cytokine storm, “Into the Eye of the Cytochrome Storm”, from Microbiol Mol Biol Rev. 2012 March; 76(1): 16–32. doi: 10.1128/MMBR.05015-11 available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294426/.
ABSTRACT
Summary: The cytokine storm has captured the attention of the public and the scientific community alike, and while the general notion of an excessive or uncontrolled release of proinflammatory cytokines is well known, the concept of a cytokine storm and the biological consequences of cytokine overproduction are not clearly defined. Cytokine storms are associated with a wide variety of infectious and noninfectious diseases. The term was popularized largely in the context of avian H5N1 influenza virus infection, bringing the term into popular media. In this review, we focus on the cytokine storm in the context of virus infection, and we highlight how high-throughput genomic methods are revealing the importance of the kinetics of cytokine gene expression and the remarkable degree of redundancy and overlap in cytokine signaling. We also address evidence for and against the role of the cytokine storm in the pathology of clinical and infectious disease and discuss why it has been so difficult to use knowledge of the cytokine storm and immunomodulatory therapies to improve the clinical outcomes for patients with severe acute infections.
Table 1
Major types and actions of cytokines
| Type | Actions |
|---|---|
| Interferons | Regulation of innate immunity, activation of antiviral properties, antiproliferative effects |
| Interleukins | Growth and differentiation of leukocytes; many are proinflammatory |
| Chemokines | Control of chemotaxis, leukocyte recruitment; many are proinflammatory |
| Colony-stimulating factors | Stimulation of hematopoietic progenitor cell proliferation and differentiation |
| Tumor necrosis factor | Proinflammatory, activates cytotoxic T lymphocytes |
Cytokine Storm Pathology
Inflammation associated with a cytokine storm begins at a local site and spreads throughout the body via the systemic circulation. Rubor (redness), tumor (swelling or edema), calor (heat), dolor (pain), and “functio laesa” (loss of function) are the hallmarks of acute inflammation. When localized in skin or other tissue, these responses increase blood flow, enable vascular leukocytes and plasma proteins to reach extravascular sites of injury, increase local temperatures (which is advantageous for host defense against bacterial infections), and generate pain, thereby warning the host of the local responses. These responses often occur at the expense of local organ function, particularly when tissue edema causes a rise in extravascular pressures and a reduction in tissue perfusion. Compensatory repair processes are initiated soon after inflammation begins, and in many cases the repair process completely restores tissue and organ function. When severe inflammation or the primary etiological agent triggering inflammation damages local tissue structures, healing occurs with fibrosis, which can result in persistent organ dysfunction.
The cytokine storm is best exemplified by severe lung infections, in which local inflammation spills over into the systemic circulation, producing systemic sepsis, as defined by persistent hypotension, hyper- or hypothermia, leukocytosis or leukopenia, and often thrombocytopenia (84). Viral, bacterial, and fungal pulmonary infections all cause the sepsis syndrome, and these etiological agents are difficult to differentiate on clinical grounds. In some cases, persistent tissue damage without severe microbial infection in the lungs also is associated with a cytokine storm and clinical manifestations that mimic sepsis syndrome. In addition to lung infections, the cytokine storm is a consequence of severe infections in the gastrointestinal tract, urinary tract, central nervous system, skin, joint spaces, and other sites.
Host Susceptibility to the Cytokine Storm
One of the challenging clinical questions about the cytokine storm is why some individuals seem particularly susceptible yet others seem relatively resistant, and there has been a great deal of interest in identifying underlying genetic mechanisms (149). Recent studies have shown a vast amount of variability in the innate immune responses of healthy humans, as reflected by the intermediate phenotype of whole-blood cytokine responses to bacterial products (151). Hyper- and hyporesponders to bacterial products are identifiable in the healthy population, which is explainable in part by genetically determined differences in the structure and function of TLR receptors, particularly TLR1 (150). In a large population of septic patients, those with a single nucleotide polymorphism (SNP) marking a hyperfunctioning variant of TLR1 had increased organ dysfunction and morbidity from Gram-positive bacteremia (150). Other genetic polymorphisms also contribute to the severity of the host response in sepsis and the cytokine storm, but the TLR1 polymorphism has a particularly strong relationship to Gram-positive infections (149).
GENOMIC VIEWS OF THE CYTOKINE STORM
Functional genomics lends itself to a deeper understanding of infectious disease by encompassing both the pathogen and the host response. Microarray technologies provide a global view of gene expression changes induced by a variety of stimuli, enabling us to simultaneously profile tens of thousands of transcriptional changes from an organ or tissue compartment. The functional associations among these gene expression patterns show perturbations in cellular signaling pathways and cellular networks, with the implication that their differential regulation may contribute toward the resolution of infection or, alternatively, have detrimental consequences leading to a fatal outcome. The compilation of cytokine and chemokine genomic data from influenza, SARS-CoV, and dengue studies provides important insight into our understanding of the cytokine storm. In particular, the dynamic transcriptional responses among the molecular components involved in cytokine and chemokine gene expression, including their kinetic properties and the timing of gene activation, are beginning to detail the events surrounding the cytokine storm.
TARGETING THE CYTOKINE STORM
Across much of the world, infectious diseases remain a very real threat, accounting for approximately half of all deaths. Malaria, tuberculosis, HIV disease, influenza, dengue, and endemic and emerging infections all contribute to morbidity and mortality. As economies develop, urbanization and environmental degradation gather pace and the structures of societies change, creating many new challenges in the 21st century. In addition to the emergence of new diseases, the continued rise of drug resistance among all the major infections is outpacing the rate of discovery of new antibiotics. Against this backdrop of antimicrobial resistance and the emergence of new pathogens, increasing interest has focused on the development of drugs that target the immune response to infection. As we have discussed, many acute infections are characterized by a powerful and potentially destructive immune response, and it would seem logical to target this response in order to reduce the self-inflicted damage initiated by the host in response to infection (129). Yet to date, successful targeting of the immune system during acute infections has proved to be extraordinarily difficult and largely unsuccessful.
