World J. Surg. 16, 53-56, 1992

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World Journal of Surgery © 1992 by the Soci~t~ lntcrnationale de Chirurgie

The Immunologic Response to Thermal Injury Mats H e i d e m a n , M . D , , Ph.D. and Anders Bengtsson, M . D . , Ph.D. Department of Surgery, Department of Anesthesiology and Intensive Care, Sahlgren's Hospital, Gothenburg, Sweden Thermal injury is associated with altered immune defense. Extensive and deep thermal injuries lead to depressed immune defense function with both cellular and humoral defense affected. There is an intricate interaction hetween various components of the immune system. The altered specific immune response is seen as a depressed ability to produce active rosette-forming cells. Depressed stimulation of lymphocyte proliferation as well as the mixed lymphocyte response have also been recorded following burns. These effects are modulated by the release of kinins, prostaglandins, anaphylatoxins, superoxides, and leukotrienes, all of Which can influence the inflammatory response following thermal injury. The humoral immunity is altered as seen by decreased levels of immunoglobulins, activation of complement with release of anaphylatoxins, and formation of membrane attacking complexes leading to inflammation and cytolysis. The immune response to burns is also affected by factors other than this injury, such as nutrition or diseases such as diabetes mellitus or disorders of the iymphoproliferative type. The immune response is also influenced by some drugs used for other reasons such as steroids, chemotherapeutic agents, and topical agents used for burn wound care. The immune reaction to a burn is also influenced by the additive effect of SUperimposed infections. Removal of injured tissue without the need for extensive transfusion will improve the ability of the burned patients to use their immune defense system in a fruitful way.

Altered immune defense following thermal injury has long been observed and studied. The results of many of these investigations are difficult to interpret as they often address a single cell, protein, or part of the response. Often the studies have made Very little attempt to fit the changes observed within the COmplex interdependence of various components of the immune system. Many of the evaluations of postburn immune alterations have been in vitro studies with the component under Study removed from the burn environment. There is an intricate Interaction between various components of the immune systems activated in this situation. Altered immune defense follOWing thermal injury contributes to the increased susceptibility of burn patients to infection. One example of this depressed immune reactivity is that patients with major burns will keep skin allografts for a period far beyond the expected rejection time [I]. Despite recent improvement in clinical care of the Patient and intervention with both specific and broad spectrum antibiotics, local and systemic infections continue to be major Causes of morbidity and mortality after burns. s Reprint requests" Mats Heideman, M.D., Department of Surgery, ahlgren's Hospitai, S-41345 Gothenburg, Sweden.

Evaluation of the I m m u n e S y s t e m

Non-Specific Immunity After burn injury the protective skin barrier is lost. This threatens our ability to coexist with the microorganisms surrounding us. When these bacteria gain access to the body a local inflammatory response usually follows, If this response does not stop the bacteria, further spread of the bacteria to the circulatory and lymphatic systems will occur. The inflammatory response will then be more generalized engaging humoral as well as cellular defense mechanisms. The success of the immune mechanisms in containing the infection depends upon many factors including previous exposure of the host to the invading microorganisms, the virulence, the growth rate, and toxin production of the organism itself. Specific Immune Response The production of antibodies and eytolytic products by B and T lymphocytes is an important component of the immune response. These lymphocytes interact in a delicate balance, influenced by helper T cells and suppressor T cells. Several authors have found extensive suppression of the cytotoxic activity of the T cells in burned patients. The peripheral blood lymphocytes from normal and thermally injured patients differ in their ability to produce active rosette-forming cells. The population of active rosette-forming cells during the first 10 days after injury is lower following extensive thermal injury compared to that in uninjured patients. The total lymphocyte count, however, does not change during this period. A correlation between the percent of active rosette-forming cells in peripheral blood and survival has been observed. A continuous decline of active rosette-forming cells over the period of study has been observed in patients who die from their injuries while patients who survive show a gradual increase to the normal range [2]. A decreased ratio of helper to suppressor lymphocytes in burn patients relative to uninfected controls has been recorded [3]. The stimulation of lymphocyte proliferation by hemagglutinin as well as the mixed lymphocyte response has been found suppressed for a long period after burns. This might be one reason for the reduced ability in these patients to avoid infections [4].

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Factors Other than the Burn Injury that Affect Immune Defences Many factors influence our ability to defend against foreign invaders and foreign material. The immune function is less active in the very young and the very old. The humoral and cell mediated immunity is also suppressed by poor nutrition [5]. Certain diseases such as diabetes mellitus and disorders of the lymphoproliferative type will also affect the immune defence systems. The extent of burn injury will influence the magnitude of immune depression. Patients with extensive deep burns have been found to have higher plasma C3a and C5a compared to patients with minor burns 1 week after injury [6]. Drugs which sometimes are used in patients with thermal injury influence the immune function. Such drugs are steroids, some of the chemotherapeutic agents, and even the topical agents used to treat the burn wounds [7]. The excision of deep burn wounds is often associated with transfusions. This has been shown to influence the infectious morbidity independent of age and burn size [8]. Altered concentrations of complement components and altered leukocyte function have been observed in association with burns [9-11]. Therapy involving the use of machines in which blood will meet large surfaces of foreign material, as during hemodialysis, the use of membrane oxygenation, or extracorporeal carbondioxide elimination, is also associated with consumption of participants of the immune defence systems [12, 13]. An old concept regarding translocation of bacteria from gut to the blood stream has been studied extensively. Infection in burn patients has been associated with disruption of normal gut barrier integrity. This has been interpreted as a systemic response to burn injury altering the gut barrier function facilitating translocation of bacteria and absorption of endotoxin [14].

Effect of Burn Injury on Cellular Immunity In response to stimulation granulocytes leave a marginated pool of leukocytes in vessels and bone marrow and appear in the circulation. Granulocytes also migrate outside the circulation as a result of chemotaxis but thereafter they will usually not return to the blood stream. The neutrophils migrate towards such stimuli as the anaphylatoxins, products of the kinin system and prostaglandin system. Several observations have been made regarding the accumulation of anaphylatoxins and prostaglandin products to the area of burn and in blister fluid. When the anaphylatoxin C5a is present in extensive amounts the leukocyte function is usually depressed, but in slightly elevated concentrations C5a will stimulate leukocyte function [15]. The prostaglandin products have been considered important following thermal injury leading to a bactericidal effect [16, 17]. Neutrophil function has been found to be abnormal in patients with burns >-45% of the total body surface area [18-22]. In patients with severe burns the opsonic index is also depressed. Neutrophils in patients with extensive burns are less able to kill Staphylococcus aareus for a long period after burn injury [4]. Other investigators have found depressed reticulo-endothelial system function and depressed phagocytic capacity of macrophages following major burns [18, 22, 23]. In association with intracellular killing, increased superoxide

World J. Surg. Vol. 16, No. 1, Jan./Feb. 1992

formation has been observed. This superoxide release in patients will be present for a long period after burn injury [4]. Several studies in animals regarding superoxide formation following burn injury and how to prevent it have appeared. Elucidative studies in humans have yet to be performed. Normal polymorphonuclear leukocytes are resting cells in the circulation. However, in association with burns there is a discharge of both primary and secondary granules [24]. An overspiU of leukotrienes has been recorded in these situations. Granulocyte dysfunction in severely burned patients has been linked to altered leukotriene generation. This will return to normal range when the patient recovers after injury [25]. High concentrations of the leukotrienes LTB4 and LTC 4 have been observed in patients with extensive thermal injuries. High concentrations have been found in plasma as well as burn blister fluid. No correlation between leukotriene peaks and the clinical course has been established [26]. Among the cytokines, tumor necrosis factor (TNF) has been found in elevated plasma concentrations following extensive burns. The serum TNF concentrations in critically ill burned patients correlate with mortality [27]. Many of the systems activated during thermal injury interact with each other or act in sequence. It is therefore a difficult task to block a single system to avoid its negative effects as other systems with similar end results then will express themselves. The Effect of Thermal Injury on Humoral Immunity

The host defense against infection is dependent on the production of antibodies by B lymphocytes and plasma cells. Many clinical studies have measured quantitative changes in serum immunoglobulin following injury [28, 29]. Decreased levels of immunoglobulins IgA, IgD, lgG and IgM have been observed in children as well as adults during the first week after severe burn injury with return to normal levels by the end of the second week. Activation of complement by thermal injury has been observed by several authors [6, 9, 30]. The anaphylatoxins C3a and C5a Will influence blood pressure, microcirculation, extravasation of fluid, and the behavior of leukocytes [31]. The anaphylatoxins will also release histamine from mast cells and basophils. Increased plasma levels of histamine have also been observed following thermal injury [32]. The latter part of the complement cascade, the membrane attacking complex, will attack not only antigen distinguished by antibodies but also cells near the activation point not related to the initial activation process (reactive lysis). The latter phenomena has been observed in association with hemolysis and anemia in septic patients [33]. This type of cytolysis might be one of the explanations for anemia observed before sepsis has occurred in association with extensive deep burns. The burned tissue will activate the complement cascade and consume some of the complement components. The remaining supply will be dependent on the balance between production and consumption. More of the complement components will be found near the injury than in areas remote from the thermally injured tissue. This can be observed if the fluid of a burn blister is analyzed for complement components and compared with the content in the fluid of joints remote from the area of burn [34,

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M. Heideman and A. Bengtsson: Immunologic Response to Thermal Injury Evaluation of Steps Taken to Diminish the Immunodepression of Extensive Burns

The thermally injured tissue is one factor depressing the immune system. Therefore excision of thermally injured tissue is of value. Steps taken to avoid bacterial colonization of the Wound are important. The advantage of excision of deep burns and closure of the burn wound results from reduction of the time during which the patient is at risk of invasive burn wound infection [36--39]. These advantages have to be balanced against the associated blood loss. A major excision and grafting procedure may require several units of blood. The less favourable effects of transfusions have been carefully studied and found to be closely related to the risk of infections [8]. Many studies in humans as well as animals have been Undertaken to see if it is possible to correct the immunologic defect that occurs following thermal injury. Several studies have identified a temporary depression of immunoglobulin in burn patients• Clinical attempts to correct this depression with intravenous immunoglobulin infusion have been performed. There have been too few controlled trials of sufficient size to demonstrate clear cut efficacy of this therapy [40]. Several reports have indicated the benefit of intensive feeding leading to reduced death in sepsis following burns [5]• • Attempts to activate the immunologic systems against bacterial invasion have been undertaken using immunopotentiators. No studies in humans have yet been reported clearly showing the effectiveness of the use of these potentiators. Since the neutrophil function is abnormal in association with extensive burn injuries, attempts have been made to improve the situation with transfusion of fresh neutrophils. However, at the present time, there are no studies proving that neutrophil transfusions in burn patients are of benefit. Great hopes have been set on the use of vaccines in patients With severe burns. No clear cut human studies have so far been able to demonstrate a significant effect by this treatment modality. As infection with Pseudomonas is a common complication in extensive burns, trials have been undertaken using PSeudomonas immunoglobulin treatment. This use has so far had no decisive effect on outcome [41]. Plasmapheresis, with the removal of altered proteins and toxins, has been studied. However, because in plasmapheresis the blood is meeting large areas of foreign material, anaphylatoxins are released with some unwanted side effects. The advantages of using this modality to influence the immune system have not yet been clearly proven. The lack of opsonins in association with trauma and burn has been extensively studied [42]. The use of fresh frozen plasma for replacement of lacking opsonins has been suggested. Clear cut StUdies in humans proving the benefit of this therapy are still awaited. It is of importance for investigators to evaluate published results with great care. Factors such as the time of study following thermal injury, the extent of thermal injury, and the Presence or absence of sepsis are crucial in studies of humans With burn injury. It is also important to analyze whether it is an in vivo or in vitro study, as well as how the described defect relates to the system as a whole and how it will influence other immune systems. The final goal must be to reverse immunologic

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alterations threatening the host and to enhance those alterations that will improve the situation for the thermally injured patient. In conclusion, the major response of the immune system to extensive deep thermal injury is depression. This host defense impairment is dependent on the extent of burn injury and has an additive effect with superimposed infections. Treatment with removal of injured tissue without the need for extensive transfusions is of benefit as is a treatment modality that prevents the addition of infection to the thermal insult. R~sum~

Les brOlures s'accompagnent d'une alteration des mEcanismes de defense immunologique. En effet, les brt~lures profondes et Etendues provoquent une diminution des fonctions cellulaires et humorales, avec des interactions entre les diffErentes composantes du syst~me immunitaire. Une des traductions de cette depression de la fonction immunologique est l'incapacitE de produire des rosettes. Chez les brfilEs, on a dEcrit Egalement une diminution de la proliferation lymphocytaire et une rEponse lymphocytaire mixte. Ces effets sont induits par ia liberation des kinines, des prostaglandines, des anaphylatoxines, des superoxydes et des leukotri~nes, substances qui peuvent influencer la rEponse inflammatoire apr~s une agression thermique. L'immunitE humorale est altErEe comme en attestent la diminution du taux des immunoglobulines, Factivation du complEment avec liberation des anaphylatoxines et la formation de complexes qui attaquent la membrane cellulaire, entrainant inflammation et cytolyse. La rEponse immune aux brfilures est Egalement affectEe par d'autres facteurs tel que l'Etat nutritionnel, certaines pathologies comme le diab~te et les maladies lymphoproiifEratives. La rEponse immune est Egalement influencEe par certains medicaments comme les corticoides, les antibiotiques et produits ~ usage local employEs dans les soins des brOlures. La reaction immune des brt~lures est Egalement perturbEe par les surinfections. L'excision des tissus ne s'accompagnant pas de transfusions importantes aidera ces patients b. garder leur capital immun. Resumen

La lesi6n tErmica se asocia con una alteraci6n en la defensa inmunitaria. Las lesiones tErmicas extensas y profundas inducen depresi6n de la funci6n de defensa inmunitaria, afectando tanto los mecanismos de defensa celular como los de defensa humoral. Existe una compleja interacci6n entre los varios componentes del sistema inmune. La alteraci6n de la respuesta inmunitaria especffica se observa como una disimunci6n de la habilidad para producir cElulas conformadoras de rosetas. Una disminuida estimulaci6n de la proliferaci6n iinfocitaria, asf como la respuesta linfocitica mixta tambiEn han sido registradas en pacientes quemados. Tales efectos son modulados por la liberaci6n de citocinas, prostaglandinas, anafilatoxinas, super6xides y leucotrienos, agentes todos que pueden influenciar la respuesta inflamatoria a la quemadura. La inmunidad humoral resulta alterada a juzgar por niveles disminuidos de inmunoglobulinas, activaci6n del complemento con liberaci6n de anafilatoxinas y formaci6n de complejos que atacan las membranas, 1o cual lleva a la inflamaci6n y la citolisis. La respuesta inmunitaria en las quemaduras tambiEn resulta

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afectada pot factores diferentes tales como desnutricirn, ciertas enfermedades como la diabetes mellitus o entidades de tipo linfoproliferativo. La respuesta inmunitaria tambirn es influenciada por ciertas drogas que se utilizan para otros proprsitos, tales como esteroides, algunos agentes quimioterapruticos y agentes de uso trpico usados para el cuidado de la herida, asi como por el efecto aditivo de una infecci6n superpuesta. La remocirn de los tejidos lesionados sin la necesidad de grandes transfusiones mejora la capacidad del paciente quemado para utilizar su sistema de defensa inmunitaria en una forma fructffera.

World J. Surg. Vol. 16, No. 1, Jan./Feb. 1992

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The immunologic response to thermal injury.

Thermal injury is associated with altered immune defense. Extensive and deep thermal injuries lead to depressed immune defense function with both cell...
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