Inflammation and Fever

The inflammatory response, or inflammation, is triggered by a cascade of chemical mediators and cellular responses that may occur when cells are damaged and stressed or when pathogens successfully breach the physical barriers of the innate immune system. Although inflammation is typically associated with negative consequences of injury or disease, it is a necessary process insofar as it allows for recruitment of the cellular defenses needed to eliminate pathogens, remove damaged and dead cells, and initiate repair mechanisms. Excessive inflammation, however, can result in local tissue damage and, in severe cases, may even become deadly.

Acute Inflammation

An early, if not immediate, response to tissue injury is acute inflammation. Immediately following an injury, vasoconstriction of blood vessels will occur to minimize blood loss. The amount of vasoconstriction is related to the amount of vascular injury, but it is usually brief. Vasoconstriction is followed by vasodilation and increased vascular permeability, as a direct result of the release of histamine from resident mast cells. Increased blood flow and vascular permeability can dilute toxins and bacterial products at the site of injury or infection. They also contribute to the five observable signs associated with the inflammatory response: erythema (redness), edema (swelling), heat, pain, and altered function. Vasodilation and increased vascular permeability are also associated with an influx of phagocytes at the site of injury and/or infection. This can enhance the inflammatory response because phagocytes may release proinflammatory chemicals when they are activated by cellular distress signals released from damaged cells, by PAMPs, or by opsonins on the surface of pathogens. Activation of the complement system can further enhance the inflammatory response through the production of the anaphylatoxin C5a. The figure below illustrates a typical case of acute inflammation at the site of a skin wound.

During the period of inflammation, the release of bradykinin causes capillaries to remain dilated, flooding tissues with fluids and leading to edema. Increasing numbers of neutrophils are recruited to the area to fight pathogens. As the fight rages on, pus forms from the accumulation of neutrophils, dead cells, tissue fluids, and lymph. Typically, after a few days, macrophages will help to clear out this pus. Eventually, tissue repair can begin in the wounded area.

Chronic Inflammation

When acute inflammation is unable to clear an infectious pathogen, chronic inflammation may occur. This often results in an ongoing (and sometimes futile) lower-level battle between the host organism and the pathogen. The wounded area may heal at a superficial level, but pathogens may still be present in deeper tissues, stimulating ongoing inflammation. Additionally, chronic inflammation may be involved in the progression of degenerative neurological diseases such as Alzheimer’s and Parkinson’s, heart disease, and metastatic cancer.

Chronic inflammation may lead to the formation of granulomas, pockets of infected tissue walled off and surrounded by WBCs. Macrophages and other phagocytes wage an unsuccessful battle to eliminate the pathogens and dead cellular materials within a granuloma. One example of a disease that produces chronic inflammation is tuberculosis, which results in the formation of granulomas in lung tissues. A tubercular granuloma is called a tubercle (shown below). Tuberculosis will be covered in more detail in Bacterial Infections of the Respiratory Tract.

Chronic inflammation is not just associated with bacterial infections. Chronic inflammation can be an important cause of tissue damage from viral infections. The extensive scarring observed with hepatitis C infections and liver cirrhosis is the result of chronic inflammation.

Check Your Understanding

Micro Connection. Chronic Edema

In addition to granulomas, chronic inflammation can also result in long-term edema. A condition known as lymphatic filariasis (also known as elephantiasis) provides an extreme example. Lymphatic filariasis is caused by microscopic nematodes (parasitic worms) whose larvae are transmitted between human hosts by mosquitoes. Adult worms live in the lymphatic vessels, where their presence stimulates infiltration by lymphocytes, plasma cells, eosinophils, and macrophages (a condition known as lymphangitis). (Source note: the source says “…eosinophils, and thrombocytes”; PathologyOutlines.com’s Filariasis reference describes the histologic infiltrate in lymphatic filariasis as “plasma cells, eosinophils, and macrophages,” not platelets/thrombocytes.) Because of the chronic nature of the illness, granulomas, fibrosis, and blocking of the lymphatic system may eventually occur. Over time, these blockages may worsen with repeated infections over decades, leading to skin thickened with edema and fibrosis. Lymph (extracellular tissue fluid) may spill out of the lymphatic areas and back into tissues, causing extreme swelling (shown below). Secondary bacterial infections commonly follow. Because it is a disease caused by a parasite, eosinophilia (a dramatic rise in the number of eosinophils in the blood) is characteristic of acute infection. However, this increase in antiparasite granulocytes is not sufficient to clear the infection in many cases.

Lymphatic filariasis affects an estimated 120 million people worldwide (Centers for Disease Control and Prevention, “Parasites–Lymphatic Filariasis,” 2016). Improved sanitation and mosquito control can reduce transmission rates.

Fever

A fever is an inflammatory response that extends beyond the site of infection and affects the entire body, resulting in an overall increase in body temperature. Body temperature is normally regulated and maintained by the hypothalamus, an anatomical section of the brain that functions to maintain homeostasis in the body. However, certain bacterial or viral infections can result in the production of pyrogens, chemicals that effectively alter the “thermostat setting” of the hypothalamus to elevate body temperature and cause fever. Pyrogens may be exogenous or endogenous. For example, the endotoxin lipopolysaccharide (LPS), produced by gram-negative bacteria, is an exogenous pyrogen that may induce the leukocytes to release endogenous pyrogens such as interleukin-1 (IL-1), IL-6, interferon-γ (IFN-γ), and tumor necrosis factor (TNF). In a cascading effect, these molecules can then lead to the release of prostaglandin E₂ (PGE₂) from other cells, resetting the hypothalamus to initiate fever (illustrated below).

Extended description

The left panel is a brain MRI with a red arrow pointing to the hypothalamus, just above the brainstem. The right panel is a flow chart, read top to bottom: an entry labeled ’exogenous pyrogens (LPS)’ has an arrow pointing down to a box labeled ’leukocytes’; the leukocytes box has an arrow pointing down to an entry labeled ’endogenous pyrogens: IL-1, IL-6, IFN-γ, TNF’; from there an arrow leads to ‘PGE2’; PGE2 has an arrow pointing down to a box labeled ‘hypothalamus’; the hypothalamus box has an arrow pointing down to a glowing oval labeled ‘fever’.

Like other forms of inflammation, a fever enhances the innate immune defenses by stimulating leukocytes to kill pathogens. The rise in body temperature also may inhibit the growth of many pathogens since human pathogens are mesophiles with optimum growth occurring around 35 °C (95 °F). In addition, some studies suggest that fever may also stimulate release of iron-sequestering compounds from the liver, thereby starving out microbes that rely on iron for growth (N. Parrow et al., “Sequestration and Scavenging of Iron in Infection,” Infection and Immunity 81, no. 10 (2013): 3503–3514).

During fever, the skin may appear pale due to vasoconstriction of the blood vessels in the skin, which is mediated by the hypothalamus to divert blood flow away from extremities, minimizing the loss of heat and raising the core temperature. The hypothalamus will also stimulate shivering of muscles, another effective mechanism of generating heat and raising the core temperature.

The crisis phase occurs when the fever breaks. The hypothalamus stimulates vasodilation, resulting in a return of blood flow to the skin and a subsequent release of heat from the body. The hypothalamus also stimulates sweating, which cools the skin as the sweat evaporates.

Although a low-level fever may help an individual overcome an illness, in some instances, this immune response can be too strong, causing tissue and organ damage and, in severe cases, even death. The inflammatory response to bacterial superantigens is one scenario in which a life-threatening fever may develop. Superantigens are bacterial or viral proteins that can cause an excessive activation of T cells from the specific adaptive immune defense, as well as an excessive release of cytokines that overstimulates the inflammatory response. For example, Staphylococcus aureus and Streptococcus pyogenes are capable of producing superantigens that cause toxic shock syndrome and scarlet fever, respectively. Both of these conditions can be associated with very high, life-threatening fevers in excess of 42 °C (108 °F).

Check Your Understanding

Summary

• Inflammation results from the collective response of chemical mediators and cellular defenses to an injury or infection.
• Acute inflammation is short lived and localized to the site of injury or infection. Chronic inflammation occurs when the inflammatory response is unsuccessful, and may result in the formation of granulomas (e.g., with tuberculosis) and scarring (e.g., with hepatitis C viral infections and liver cirrhosis).
• The five cardinal signs of inflammation are erythema, edema, heat, pain, and altered function. These largely result from innate responses that draw increased blood flow to the injured or infected tissue.
• Fever is a system-wide sign of inflammation that raises the body temperature and stimulates the immune response.
• Both inflammation and fever can be harmful if the inflammatory response is too severe.

Key terms

• inflammation — innate nonspecific immune response characterized by erythema, edema, heat, pain, and altered function, typically at the site of injury or infection but sometimes becoming systemic.
• erythema — redness at the site of inflammation, usually due to dilation of blood vessels in the area to help bring in white blood cells.
• edema — swelling due to accumulation of fluid and protein in tissue as a result of increased permeability of capillary walls during an inflammatory response; chronic edema can also result from blockage of lymphatic vessels, as in the case of elephantiasis.
• granuloma — walled-off area of chronically inflamed tissue containing microbial pathogens, macrophages, and cellular materials unable to be eliminated.
• fever — system-wide sign of inflammation that raises the body temperature and stimulates the immune response.
• pyrogens — chemicals that effectively alter the “thermostat setting” of the hypothalamus to elevate body temperature and cause fever.
• crisis phase — point at which a fever breaks, reaching a peak before the hypothalamus resets back to normal body temperature.

Practice

Identify the signs of inflammation and fever and explain why they occur

Explain the advantages and risks posed by inflammatory responses

This section is adapted from Microbiology, Section 17.5: Inflammation and Fever by Nina Parker, Mark Schneegurt, Anh-Hue Thi Tu, Philip Lister, Brian M. Forster, and OpenStax, © OpenStax, licensed under CC BY-NC-SA 4.0. Access the original for free at openstax.org. Changes: all four source figures re-encoded as WebP and rendered as mediafigures; the Erythema and Hypothalamus figures given explicit kind="diagram" and the Granuloma and Elephantiasis figures kind="photo" after image inspection (the manifest guesses from file type, which is a JPEG for all four); all four source alts rewritten from the images after inspection, and a longdesc added to the Hypothalamus figure’s multi-step flow chart, which the caption does not walk through; the module’s cross-reference to Bacterial Infections of the Respiratory Tract (a chapter well beyond this run’s mapped chapters 17–18, not yet authored) is left as plain text naming the section, per the book’s rule for a target outside the mapped chapters; the source’s “Go back to the previous Clinical Focus box” link is rendered per this run’s chain convention as “The case began in [Physical Defenses],” an absolute site-root Markdown link naming Section 17.1 rather than the immediately preceding Section 17.3; the two source footnotes are rendered as inline parenthetical citations after the sentences they support — the Parrow et al. citation verbatim (it carries no URL), and the CDC lymphatic filariasis citation with its bare access URL dropped, its access date kept, and its one-word title typo (“Filiariasis”) corrected to “Filariasis” in place, without an inline note; of the module’s two body Check Your Understanding boxes (four bullets total), three are graded and the fourth stays a self-check: “Name the five signs of inflammation” and “Is a granuloma an acute or chronic form of inflammation? Explain” become multiple-choice items, each keyed to the one sentence that names the signs or defines a granuloma, with distractors built from the module’s own neighboring terms; “Explain the difference between exogenous and endogenous pyrogens” becomes a multiple choice keyed to the module’s classifying sentence, written without the sentence’s own molecule names so it does not anticipate the Practice sortbins built from the same sentence; “How does a fever inhibit pathogens?” stays a self-check, since its honest answer needs both of the module’s fever-and-pathogen-growth sentences; of the section’s one Short Answer and two Critical Thinking questions, none has a source key and none is dropped: the Short Answer (“Differentiate exogenous and endogenous pyrogens, and provide an example of each”) is rendered as a sortbins exercise, sorting the module’s own named examples (LPS; IL-1, IL-6, IFN-γ, TNF) into the exogenous/endogenous bins the same sentence pair names — a different fact (the examples) from the body item beside it (the definition), so the two are not a duplicate; both Critical Thinking questions (the septic-shock therapies question and the Lübeck tuberculosis-vaccine question) stay self-checks, since the module prints no therapies or defenses list for either and each model answer says only what this module’s own sentences support and stops — the septic-shock model answer draws on this same section’s Clinical Focus resolution (the only inflammatory-pathway therapy the module names anywhere), and the tuberculosis model answer draws on this section’s own granuloma, fever, and iron-sequestration sentences; key terms compiled from the module’s seven defined terms and the book’s Glossary appendix, with one (pyrogens) taken from this module’s own defining sentence because the appendix has no entry for it; PGE₂ is set in Unicode subscript in prose, since a grep of chapters 1–16 found no prior house form for it in this book and it takes the same CO₂-style treatment as other chemical subscripts; inside the Hypothalamus figure’s alt and longdesc, “PGE2” is spelled with a plain digit, since attributes cannot hold Unicode formatting the way prose subscripts can; the module’s two body-figure cross-references (to the Granuloma and Elephantiasis figures) are rendered as “shown below”/“illustrated below” rather than by print figure number; the Micro Connection box’s list of cells infiltrating filarial lymphatic vessels is corrected from the source’s “lymphocytes, plasma cells, eosinophils, and thrombocytes” to “…and macrophages,” with a visible Source note, since platelets are not a recognized component of this infiltrate and PathologyOutlines.com’s Filariasis reference names macrophages as the fourth cell type instead. No source exercise item is omitted; the Hypothalamus figure’s source alt describes an additional IL-6 production path, a circumventricular-organs label, and a negative-feedback loop that the drawn artwork does not show, so the alt and longdesc describe only the linear cascade actually drawn; the Granuloma figure’s source alt describes a single circular structure where the artwork shows two circular clusters, and the alt names both.