INTRAVENOUS IMMUNOOLOBULAN IN SEVERELY BURNED PATIENTS FIVE YEARS OF SUCCESSFUL EXPERIENCE

Oliva R.G., Sica I.

Burn Unit, Juan A. Fernandez Hospital, Cervifio 3356, Buenos Aires, Argentina

SUMMARY. Tlis report is a retrospective study of the therapeutic benefit of parenteral administration of an intravenous immunoglobulin (IVIG) preparation for reducing infectious complications in 202 thermally injured patients. All the patients received a complex therapy that included in 67 patients high doses of IVIG. The efficacy of the treatment was evaluated according to the frequency and localization of the infections, clinical response to anti-infectious therapy, duration of the infectious process, overall time of hospitalization and mortality rate. The results demonstrate that patients treated with IVIG in addition to antibiotic therapy had a significant reduction in mortality due to infections. The patients recovered faster (50% reduction in hospitalization time) from the thermal injury.

Infection remains the most frequent cause of death in burn patients who survive the initial insult of the thermal injury (1). Development of infection results from one of two main factors: the presence of a pathogenic agent with enough virulence to colonize the host, and/or a particular state of immunodeficiency in the host so that his bacterial saprophyte flora can develop and turn virulent. In most cases a combination of these two factors is observed (2,3).
In severely burned patients, the first barrier against bacterial entrance, the cutaneous barrier, is lost or severely affected so that the second barrier, the immune system of the body, becomes the main defence against infection (4,5,6). Both the humoral and cellular components of this system participate in the fight. However, it is well known that large burns are associated with a severe immune dysfunction: tl-ds imimmosuppression affects all components of the immune system including T-cell, granulocyte and phagocyte function. Serum immunoglobulin levels are severely depressed in large bum injuries especially during the first week. For these reasons, there have been some therapeutic attempts to stimulate the immune system with various immunomodulating agents (7) and nutritional support (8). Replacement therapy with modified or intact immunoglobulins has also been reported (9,10).
This report is a retrospective study of the therapeutic benefit of parenteral administration of an intravenous immunoglobulin (IVIG) preparation for reducing infectious complication in 202 thermally injured patients.

From a total of 498 patients hospitalized in our Burn Unit at the Juan A. Fernandez Hospital between January 1987 and July 1991, 162 clinical histories from patients belonging to Class III and IV of severity were analysed. We included another 40 patients studied in our first experience, during 1986. This totalizes 202 patients, 16-93 years old, 145 male and 57 female. They were assisted at variable times after the bum episode, ranging from one hour to 18 days.
All the patients received a complex anti-infectious therapy that included, in 67 patients, high doses of IVIG. 100 mg/kg/day of Endobulin (Immuno AG) was administered three times a week until control parameters suggested a change in the patient's class of severity.
The following evaluation criteria were used: nutritional (weight, dosage of albumin and cholesterol), immunological (dosage of serum immunoglobulins, electrophoretic proteinogram. and peripheral lymphocyte count), infectological (bacteriological culture with hyssop and punch with homogeneization of the samples and quantification of the infection).
The efficacy of the treatment was evaluated according to the frequency and localization of the infection, clinical response to anti-infectious therapy, duration of the infection process, overall time of hospitalization and mortality rate.

Fig. 1 Fig. 2

Fig. 1 shows the mean increase of serum IgG in six patients treated with IVIG as compared with IgG levels of patients treated with conventional therapy only (control group). The differences found between both groups are statistically significant.
In the course of the treatment, 53 patients died (26%). The causes of mortality are recorded in Fig. 2. It was observed that the most frequent cause of death during the first week of evolution was cardiopulmonary arrest (Fig. 2a), whereas sepsis was the main cause of mortality in patients who survived the first week of treatment (Fig. 2b). Overall cause of mortality is shown in Fig. 2c, where it can be seen that sepsis accounts for more than 50% of patient deaths.
The efficacy of IVIG treatment in terms of reduction of mortality in shown in Table 1: 34. 1 % of control patients died as compared to 10.4% of IVIG treated patients. This reduction is very significant (p < 0.001).

Patient distribution according to group'of severity gave similar good results. Table II illustrates the effect of IVIG treatment on sepsis mortality in patients from Class 111 and IY Most of the deaths occurred in Class IV: 32.2% were from control patients as compared to 4.76% from the treated patients.

The efficacy of the treatment is also reflected in a significant reduction of hospitalization time (Table 111); treated patients from Class III stayed 50% less time in hospital than control patients, and patients from Class IV receiving IVIG benefited with a 32% reduction in hospitalization time.

In severely burned patients scrum immunoglobulins are depressed owing to an increased rate of disappearance, especially of IgG (11). This may be due to several factors, including increased catabolism, given the hypermetabolic state of the burn patient and the loss of serum immunoglobulins by wound exudates.
This condition, together with the loss of the skin barrier, makes the burn patient very susceptible to infections. In fact, this remain the most frequent cause of death among these patients (1).
The clinical use of immunoglobulins started in the 1950s, after the Second World War. These products were for intramuscular use and were indicated in the prevention of viral infections. Later this was extended to patients with severe immunodeficiencies (12). The introduction in the 1970s of immunoglobulins for intravenous use allowed their administration in higher doses. The first preparations were elaborated with methods that included proteolytic enzymes that degraded the molecule to avoid side-reactions, frequently observed in previous preparations (13); later on, methods that maintain the integrity of the molecule were developed but they were chemically modified (14). The most recent advances are products that contain intact and unchanged molecules of immunoglobulin that preserve all the properd biological functions of native proteins (15). They are the so-called third-generation immunoglobulins.
Replacement therapy in burn patients with intact or modified IVIG containing a wide spectrum of antibodies against a variety of common pathogens resulted in elevation of serum immunoglobulins (9,10). However, no success was obtained in terms of reduction of infections and/or mqrtality rate (10).
In this report we present data comparing the efficacy of a complementary IVIG treatment (third-generation immunoglobulin) to conventional therapy in severely burned patients.
We were able to demonstrate that patients treated with IVIG in addition to antibiotic therapy had a significant reduction in mortality due to infections (Table 11). We interpret that this was due to a faster recovery of the patients (50% reduction in hospitalization time) that enabled us to "rescue" some patients from exposure to pathogens.
We believe that, in addition to proper hydration of the patient, early escharectomy and grafting, and specific antibiotic therapy, the administration of intravenous immunoglobulin is an invaluable tool in the management of bum patients.

RESUME. Cet article est une étude rétrospective sur les avantages thérapeutiques de l'administration parentérale d'une préparation intraveineuse d'immunoglobuline (IVIG) pour réduire les complications infectieuses chez 202 patient brûlés. Tous les patients ont re~u une thérapie complexe qui incluait, pour 67 patients, des doses élevées d'IVIG. Uefficacité du traitement a été évalué selon la fréquence et le site des infections, la réaction clinique à la thérapie anti-infectieuse, la durée du procès infectieux, la période complessive de l'hospitalisation et le taux de mortalité. Les résultats montrent que les patients traités avec IVIG en plus de la thérapie antibiotique ont présenté une réduction significative de la mortalité due aux infections. En outre, les patients ont guéri plus rapidement des lésions causées par la brûlure (réduction de 50% dans la période de l'hospitalisation).

BIBLIOGRAPHY

1. Sevitt S.: A review of the complications of burns, their origin and importance for illness and death. J. Trauma, 19: 385, 1979.
2. Alexander J.W., Meakins J.L.: A physiological basis for the development of opportunistic infections. Ann. Surg., 176: 273, 1972.
3. Pruitt B. et al.: Opportunistic infections in severely burned patients. Am. J. Med., March: 146, 1984.
4. Kohn J., Cort D.F.: Immunoglobulins in burned patients. Lancet, 1: 836, 1969.
5. Munster A., Eurenius K. et al.: Cell mediated immunity after thermal injury. Ann. Surg., 177: 13, 1973.
6. Munster A.: Immunologic response of trauma and bums. Am. J. Med., March: 142, 1984.
7. Wayinack J.P., Jenkins M. et al.: A prospective study of thymopentin in severely burned patients. Gynecol. Obstet., 164: 432, 1987.
8. Alexander JW: Nutrition and infection: new perspectives for an old problem. Arch. Surg., 121: 966, 1986.
9. Shirani K.Z., Vaughan G. et al.: Replacement therapy with modified immunoglobulin G in burn patients: preliminary kinetic studies. Am. J. Med., March, Suppl. 3A, 76: 175, 1984.
10. Waymack J.P., Jenkins M. et al.: A prospective trial of prophylactic intravenous immune globulin for the prevention of infections in severely burned patients. Burns, 15: 71, 1989.
11. Arturson G., Mogman C.F. et al.: Changes in immunoglobulin levels in severely burned patients. Lancet, 1: 836, 1969.
12. Janeway C.A., Rosen F.S.: The gammaglobulins. IV. Therapeutic uses of gaminaglobulin. N. Eng. J. Med., 275: 826, 1966.
13. Sgouris LT: The preparation of plasmin treated immune scrum globulin for intravenous use. Vox Sang., 32: 175, 1967.
14. Stephan W.: Beseitigung der Komplemententlixierung von Gammaglobulin dutch chemische Modifizierung mit B-propionolacton. Klin. Chem. u Klin. Biochimie, 7: 282, 1969.
15. Eibl M. et al.: Safety and efficacy of monomeric, functionally intact intravenous IgG preparation in patients with primary immunodeficiency syndrome. Clin. Immunol. Immunopath., 31: 151, 1984.