Septicemia and Sepsis:
P.K. Ghatak, MD
These two terms are often used interchangeably but they do not covey the same meaning. Septicemia means tissue damages from blood-borne pathogens – primarily bacteria or viruses. Sepsis indicates tissue damages from released of Cytokines, TNF and inflammatory Interleukins from the accumulated blood cells and immunocytes at the site of infection.
Septicemia:
Whenever a harmful agent gets inside the body, the body tries to put a barrier around it so that the harmful agent does not spread to other parts of the body. But due to a number of reasons, this may fail. And if the agent a biological agent, it invades tissues widely and enter the blood stream. The presence of live biological pathogen and damage produce by its toxins is called septicemia.
Our body is pre-programmed to repose by a set pattern of actions called 1. Innate or inherited immune reaction. 2. And by a separate set of actions, from experience gained from encounters with the offending agents, called Acquired Immune reaction.
1 Innate reaction :
The skin, surface layer of the nose, mouth, GI, Respiratory and Genitourinary tracts are the physical barriers to invaders. Once that defense is breached, then the responsibilities fall on the surveillance cells for finding the invaders by the immune cells called Dendritic cells. Dendritic cells recognize the molecular patterns of the invaders' surface membrane, and the dendritic cells attach themselves to it, like a key fits a lock. Then, these immune cells release chemicals, called Cytokines. In repose to cytokines, neutrophils, monocytes, eosinophils, phagocytes and complements (present in plasma) gather at the site. And a series of actions and reactions take place in the local area resulting in increased blood flow, redness, swelling, temperature elevation and temporary loss of function.
This is called, Classical Pathway. Other paths are - Alternate Pathway and Mannose-Lectin Pathway. These pathways are activated when the invaders are yeasts, viruses and certain other groups of bacteria.
The end result of all pathways are that the same. The invasion is checked, the invaders are paralyzed and eaten alive by the macrophages, and the dead bodies are removed from the area in order for healing to take place.
Adaptive Immune Reaction:
Acquisition of adaptive immunity is a learned process. During the first encounter with a pathogen, a signature part of the pathogen - usually, a protein molecule called antigen is recognized by the dendritic cells and the information is passed in succession to lymphocytes of various designations like B-cells, T-cells and ultimately to antibody producing B-lymphocytes. B-cells produce immunoglobulin, specific for that antigen, which when combines with that antigen of the invader, it neutralizes the pathogen. This antigen remains in memory in a subset of B -cells called Memory cells. These lymphocytes live in the regional lymph nodes and the duration of memory is temporary, whereas those B-memory cells move to the bone marrow retain memory permanently.
Like innate immunity, adaptive immunity also consists of a cellular component and a Humoral component.
One can well appreciate there are plenty of opportunities for the invading pathogens to neutralize or evade this body's defense system due to systemic illness or congenital immune deficiencies or use of immune modifying medications or any combination of these. These conditions favor onset of septicemia.
Sepsis:
Sepsis is a severe clinical condition and carries a mortality over 50 %. The inflammatory reactions mentioned in Septicemia are operative here also but in aggressive and unregulated manner in sepsis. During COVID-19 endemic, the high death rate was due to this process and Cytokine Storm term was used to describe this phenomenon. In sepsis, failure of the heart, lungs, kidneys, brain and liver occurs together. A paper published on sepsis based on worldwide case studies, showed Gram negative infection accounted over 50% of sepsis, and gram positive bacteria, fungi and viruses accounted for the rest. The source of infection in order of frequency were the lungs, abdomen, and urinary tract and the underlying conditions that favors sepsis were diabetes mellitus, congestive heart failure, renal failure.
Mechanism.
Most harmful pathogens carry potent endo and exotoxins. These toxins act in many ways to kill or paralyze immune cells and cause tissue injury. Adhesion of endothelial lying cells are weakened and pathogen and toxins gain entry in the organs and continues to damage tissue. White blood cells in their cytoplasm have powerful enzymes in packets called granules and released enzymes are primarily directed towards the pathogens but when produced in excess amount it kills normal cells also and contribution organ damage. In addition, in sepsis major alteration in the concentration of blood coagulation factors takes place due to its effect on liver and local tissue. This causes hemorrhage and also decimated intravascular coagulation and rapid organ failure.
Effect of sepsis.
Vascular wall damage and derailed maintenance of vascular tones and depressed cardiac output produces hypotension and change in consciousness or unconsciousness. Blood flow through the lung capillaries diminishes markedly, producing hypoxia, generation of oxygen radicals and superoxides and more tissue necrosis. Similar changes in the kidneys produce renal failure and electrolyte imbalance.
Role of Macrophages in Sepsis.
Macrophages are of 3 types - resident tissue macrophages (RTMs), monocyte-derived macrophages (MDMs), and transitioning MDMs in the tissue.
Macrophages express a number of proinflammatory chemokines and cytokines, including IL-1β, IL-6, IL-8, CXCL10, and TNFα. And a macrophage subset termed Macro_c2-CCL3L1, which specifically expressed CCL8, CXCL10/11, and IL-6, and a monocyte subset termed Mono-c1-CD14-CCL3, which abundantly expressed IL-1β, CCL20, CXCL2, CXCL3, CCL3, CCL4, and TNF alpha.
Macrophage hyperactivation.
Hyperstimulated macrophages produce Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome. Hemophagocytosis (i.e., engulfment of erythrocytes by activated macrophages), systemic inflammation, fever, cytopenia, hyperferritinemia, and hyperlipidemia, which can be due to inherited defects in cytotoxic T-cell function or triggered secondary to infection or rheumatological disorders.
Role of Platelets in Sepsis. Platelets are tiny lens like discs and platelets have no nucleus but the cytoplasm is packed with powerful chemicals in packet from. Though platelets lack in size but make that up in numbers, around 200,000/microlit of blood. In inflammation and specially in Sepsis, cytokines induce rapid release of platelets from the bone marrow and make individual platelet swell and the surface becomes more sticky and adhere to each other into tiny clots and blocks blood flow in capillaries. This leads to ischemia and tissue necrosis of the kidneys, liver, brain and lungs. Arterial blood fails to load up oxygen and all highly vascular tissues fail to function normally and contribute to necrosis. Released chemicals from platelets recruit further inflammatory cells at the site.
Cytokines in Sepsis.
LTB4. Promotes the release of inflammatory cytokines, recruits neutrophils, increases neutrophil chemotaxis, causes degranulation of neutrophils, increases interaction between neutrophils and endothelial cells, stimulates the release of mediators, enzymes and superoxide, increases ( Interleukin) IL 6, increases pain perception by lowering pain receptors threshold.
ILs are stimulators of inflammation.
These ILs are IL-1, IL-6, IL-12, IL-18 and IL-23
The most pro-inflammatory Cytokines are IL-1 beta and TNF alpha.
Pro-inflammatory ILs activate CD2, CD4, CD8, CD27, CD134 and CD137.
Inhibitors of inflammation ILs are-
IL-10, IL-6, IL-1 beta. They activate CD80, CD152, CD160, and CD223.
Interleukins are secreted primarily by immunocytes. Interleukins (ILs) are hormones like chemicals, function as an inflammatory promoter but also act as anti-inflammatory agents. In the biological system, pro and anti, inflammatory agents are neither good nor bad. Both are required to fight infections, autoimmune diseases and cancers and at the same time must be available for repairs of diseased or damaged tissues. Interleukin 6 (IL-6) is the main Interleukin in the pathogenesis of COID-19 virus inflammatory reactions. 1. IL-6 promotes inflammation. 2. Anti-inflammation. 3. Pathogen clearance. 4. New blood cell formation (hemopoiesis) 5. Reset the metabolic rate of the body. 6. Modification of lipid metabolism. 7. Neural differentiation increased substance-P generation and myelin sheath break-up.
Prostaglandins in Sepsis.
Prostaglandins are produced by a number of cells, some are immunocytes others are not immunocytes. It is derived from Arachidonic acid. PGI2 is a potent vasodilator, and an inhibitor of platelet aggregation, leukocyte adhesion, and prevents smooth vascular muscle proliferation. PGI2 receptors are expressed in the kidney, liver, lung, platelets, heart, and aorta. PGD2 is synthesized in both the central nervous system (CNS) and peripheral tissues. In the brain, PGD2 regulates sleep and pain perception.
