Symposium on Surgical Aspects of Immunology
Overwhelming Postsplenectomy Infection William Krivit, M.D., Ph.D.,'~ G. Scott Giebink, M.D., t and Arnold Leonard, M.D., Ph.D. t
Splenectomy done at any age and for any reason increases the risk for death due to overwhelming bacterial infection. Postsplenectomy infection has a rapid onset and a mortality rate of 50 per cent that distinguishes it from other bacterial infections. The immune aberration following splenectomy includes decreased serum lgM levels, altered serum opsonic function, and failure to respond to intravenous particulate antigen challenge. The risk for overwhelming postsplenectomy infection in individuals splenectomized for trauma is 50-fold greater than for the normal population and is considerably greater following splenectomy for idiopathic thrombocytopenia, acquired hemolytic anemia, Hodgkin's disease, and other hematologic disorders. The first step in preventing overwhelming postsplenectomy infection is to review surgical indications for splenectomy so that the conservative management of patient's disease will be heavily considered. Included in the surgical armamentarium should be techniques of splenic repair in cases of trauma, awareness of the syndrome of overwhelming postsplenectomy infection and need of penicillin prophylaxis and pneumococcal vaccination. Autosplenic transplantation (splenosis) has been suggested as a method for providing intrinsic spleen tissue, which can prevent overwhelming postsplenectomy infection. However, clinical proof ofthe effectiveness of splenosis is still lacking. The syndrome of overwhelming postsplenectomy infection has become well identified and accepted within the past few years. One of the major reasons for this change has been the extensive review by Singer in 1973. 39 His collection of data clearly gave form and substance to a unique syndrome. An update of this material by Krivit in 1977 summarized the immunologic data relating to lgM deficiency following splenectomy. 16 '''Professor of Pediatrics, University of Minnesota Medical School and Hospitals, Minneapolis, Minnesota t Assistant Professor, Department of Pediatrics, University of Minnesota Medical School and Hospitals, Minneapolis, Minnesota ~Professor, Department of Surgery, and Head, Division of Pediatric Surgery, University of Minnesota Medical School and Hospitals, Minneapolis, Minnesota Supported by grants Al-08821, CA-21737, and HL-07145, from the National Institute of Health.
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The use of splenectomy as a therapeutic measure rests in surgeons' hands. This article addresses the problems and potential solutions tha~ face the surgeon. Indeed, this is most appropriate since surgeons have been in the forefront of research on overwhelming postsplenectomy infection. Morris and Bullock in 1919 were first to predict that removal of the spleen would result in an increased susceptibility to infection. 27 King and Schumacher in 1952 stimulated interest of many concerning overwhelming postsplenectomy infection in patients with hereditary spherocytosis. 14 In 1957 Smith presented his data on postsplenectomy infection in patients with thalassemia. 40 Our experience and later review at the University of Minnesota were the first to support Smith's conclusions. 21
CLINICAL CHARACTERISTICS Description of Syndrome The characteristic events in overwhelming postsplenectomy infection are the sudden onset of nausea, vomiting, and confusion leading to coma, and often proceeding to death within hours. The case fatality rate is 50 to 75 per cent in all series studied. The infecting organism most often recovered from patients with overwhelming postsplenectomy infection is S. pneumoniae. In decreasing frequency, N. meningitidis, E. coli, H. in:fluenzae, and S. aureus are found. Virus infection was noted in the original description of overwhelming postsplenectomy infection. Evidence of disseminated intravascular coagulation, severe hypoglycemia, electrolyte imbalance, and shock are frequently noted. Diplococci are often seen on peripheral blood smears in patients with overwhelming postsplenectomy infection. Blood cultures frequently yield 106 bacteria per ml of blood, a concentration far in excess of the bacteremia that accompanies pneumonia and other ordinary infections. 45 At autopsy, the observations are typical for septicemia but also include adrenal hemorrhage (Waterhouse-Friderichsen syndrome) in a high proportion of cases. Therapy, therefore, must be vigorous with immediate and intensive antibiotic usage, and extensive supportive fluid and electrolyte management. Traumatic Rupture of Spleen The patient who undergoes splenectomy because of abdominal trauma serves as the prototype for this discussion because these patients have no underlying immunologic or hematologic disease. Sufficient reports of overwhelming postsplenectomy infection subsequent to trauma provide appropriate data to make this a significant concern for surgeons. Our report 4 and those of others have been summarized. 16 At least 21 individuals have been enumerated in the literature who have had overwhelming postsplenectomy infection following splenectomy for trauma. Their ages ranged from 7 to 50 years at the time of infection. The interval between splenectomy and infection ranged from 7 months to 25 years. Case fatality was 67 per cent. To establish the true risk of patients developing overwhelming postsplenectomy infection requires knowledge of the incidence of severe
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bacterial infections in a normal nonsplenectomized population. The baseline data for normal individuals was obtained from comprehensive epidemiologic health survey in Newcastle-Upon-Tyne, England. In this survey, 84 7 children were followed during the first five years oflife; 0. 7 per cent had bacterial meningitis or sepsis during the observation period. 39 Mortality owing to sepsis was 0.01 per cent. The incidence of overwhelming postsplenectomy infection following splenectomy for trauma is 10 of 688 or 1.45 per cent, and mortality owing to sepsis is 0.58 per cent. 39 Statistical considerations are important in understanding the risk of splenectomized patients. Many surgeons have seen overwhelming postsplenectomy infection and are convinced of its validity. Others have splenectomized patients without ever seeing overwhelming postsplenectomy infection. The latter circumstance is not surprising since the overall incidence of overwhelming postsplenectomy infection is relatively low. It would be anticipated that within small series of splenectomized patients, no cases of overwhelming postsplenectomy infection would be seen; but to conclude that splenectomy does not result in an increased risk of overwhelming postsplenectomy infection after reviewing, for example, 60 patients is statistically unwarranted. The conclusion here is that the overall incidence of overwhelming postsplenectomy infection in patients splenectomized for trauma must carry more weight than the small negative series. Fortunately, more centers have carefully reviewed their splenectomized patients, and there is increasing general agreement regarding the reality of overwhelming postsplenectomy infection subsequent to splenectomy at any age and for any disease.
Hereditary Spherocytosis The immune system in hereditary spherocytosis is normal, and there is minimal reticuloendothelial system disease from hemolysis. To date, overwhelming postsplenectomy infection has not been reported in a nonsplenectomized individual with hereditary spherocytosis. Yet, numerous instances of overwhelming postsplenectomy infection have been reported following splenectomy for this condition. The syndrome of overwhelming postsplenectomy infection has been documented in 3. 5 per cent of children splenectomized for hereditary spherocytosis. 39 Schilling reported an overwhelming postsplenectomy infection in one child. 34 Adults splenectomized for hereditary spherocytosis also die from overwhelming postsplenectomy infection. 32 Hodgkin's Disease With the modern technique of staging Hodgkin's disease by laparotomy and splenectomy and with the increased use of chemotherapy and radiation, the syndrome of overwhelming postsplenectomy infection has been observed. It is not known whether this sudden surge of an hitherto unrecognized complication of Hodgkin's disease is owing to splenectomy or to chemotherapy and radiation treatment for the disease. Chilcote reviewed 200 children and young adolescents with Hodgkin's disease for Children's Cancer Study Group. 7 The incidence of overwhelming postsplenectomy infection was 10 per cent with an overall mortality of
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5 per cent. Subsequently, in the several centers in which penicillin prophylaxis· has been instituted, overwhelming postsplenectomy infection has not occurred despite continuation of prior therapeutic maneuvers. This suggests that splenectomy and not radiation or chemotherapy is the cause of overwhelming postsplenectomy infection in Hodgkin's disease, s-ince treatment is essentially identical to that before the use of penicillin. A review of the problems concerning splenectomy in Hodgkin's disease is forthcoming. 17
Renal Transplant At the University of Minnesota, splenectomy at the time of bilateral nephrectomy had been done in order to increase immunologic acceptance of renal transplant. Four children with severe pneumococcal infections have been reported in a population of approximately 120 children under the age of 16 who had undergone transplantation. Two had severe meningitis, one had septic arthritis, and one succumbed to overwhelming pneumococcal sepsis. 23 At present, because of these circumstances, penicillin prophylaxis is now being used in all splenectomized children. Another series has also been reported, indicating occurrence of overwhelming postsplenectomy infection in siinilar situations. 35 Other Clinical Conditions Patients with sickle cell anemia are quite susceptible to overwhelming postsplenectomy infection because of autosplenectomy intrinsic to the basic disease process. Congenital asplenia is easily diagnosed because of characteristic heart disease and the presence of Howell-Jolly bodies. This hematologic finding is always found post splenectomy if there is a complete removal of all splenic tissue. Statistical considerations regarding the syndrome of overwhelming postsplenectomy infection in these two conditions are similar to those in surgical splenectomy. In addition, there are numerous instances of overwhelming postsplenectomy infection in patients who have underlying disturbance of the reticuloendothelial system. IMMUNOLOGIC ASPECTS OF SPLENECTOMY Humoral Immune Function Several lines of evidence suggest that the splenectomized host has compromised humoral defenses. Both immunoglobulin and complement deficiencies have been reported in these patients. Immunoglobulins Antibody response to intravenously administered particulate antigens is reduced post splenectomy. Splenectomized humans did not form hemolysin antibody to intravenously administered sheep red blood cells. 33 Antibody responses to primary intravenous immunization with a bacteriophage 8 x 174 is decreased despite normal clearance of these particulate antigens. 43 This observation suggests that the nonsplenic por-
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tion of the reticuloendothelial system adequately compensates mechanically for the loss of the spleen, but that antibody formation in these nonsplenic sites is less efficient than in the spleen. Asplenic individuals also were shown in this report to have an inability to switch from IgM to IgG antibody production. In every series reported, the average serum IgM level in splenectomized patients is significantly depressed below the normal range. 16 That the IgM depression is owing to the splenectomy and not to the underlying disease process is best exemplified in traumatic rupture of the spleen. In adults, the average and standard deviation oflgMlevelin splenectomized group was 94 ± 48 (n = 22) as compared with 159 ± 74 (n = 67) in agematched non splenectomized controls. 24 In another study in children, the IgM level post splenectomy for traumatic rupture of spleen was 58.7 ± 31.0 (n = 31) compared with 93.4 ± 46.8 in normal children of all ages. 16 IgG and IgA immunoglobulins frequently are either elevated or normal in splenectomized patients. 16 The pattern of immunoglobulin concentration is unrelated to the depression oflgM. Limited data collected to date on IgD have not revealed any specific deficiencies, and only a few reports of IgE levels are noted. Host defense against most pathogenic bacteria involves opsonization, a serum function requiring antibody and complement, for efficient phagocytosis to occur. Although antibody alone can be opsonic for some organisms, opsonization is markedly enhanced by complement. 12 Since most pneumococci are efficiently opsonized via the alternative complement pathway, 9 • 12 and because type-specific antibody may not be required for activating this pathway, the alternative pathway may represent the principal mechanism for pneumococcal opsonization in the nonimmune host. Accordingly, complement deficiencies might seriously impair opsonization and reduce host resistance to invading pneumococci. Carlisle and Saslaw 6 were the first to report diminished properedin activity, an altemative complement pathway factor, in asplenic humans. Polhill and Johnston 30 observed significantly reduced alternative complement pathway function in about 20 per cent of asplenic humans. Depressed complement function is not universal in these patients since others have found normal levels of complement in asplenic patients. The net effect of impaired antibody formation and of complement dysfunction may reduce serum opsonic activity in some patients. However, Winkelstein et alY and Giebink et al." were unable to show diminished serum opsonic activity for several pneumococcal types in asplenic patients. However, after subcutaneous immunization with pneumococcal vaccine, asplenic patients failed to increase their serum pneumococcal opsonic activity in concordance with increased antibody levels! Normal control patients showed concordance between antibody and opsonic levels.
Cellular Immune Function The number of circulating T lymphocytes is somewhat reduced following splenectomy. 2 • 34 Lymphocyte mitogen proliferative response was
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decreased for a period of time and then became normal. Polymorphonuclear leukocyte functions and C3 levels were not changed in asplenic patients.34
PENICILLIN (ANTIBIOTIC) PROPHYLAXIS Because overwhelming postsplenectomy infection is caused by pneumococci in 50 per cent of cases, penicillin prophylaxis has been successful in effectively reducing the incidence. Lanzkowsky demonstrated that penicillin prophylaxis eradicated the syndrome of overwhelming postsplenectomy infection in his institution, whereas the incidence before penicillin usage was 5 per cent. 18 Two patients who were not taking prescribed penicillin succumbed to overwhelming postsplenectomy infection. In another review, overwhelming postsplenectomy infection occurred in 10 per cent of children who underwent laparotomy and splenectomy for Hodgkin's disease with an associated mortality of 5 per cent. 7 Overwhelming postsplenectomy infection was not found in any of the member institutions using penicillin prophylaxis for all their patients with Hodgkin's disease. Subsequently, many more institutions began utilizing penicillin prophylaxis, and in a recent informal review, none of the polled physicians had observed cases of overwhelming postsplenectomy infection. Compliance for daily penicillin ingestion for 5 to 10 years, if not for life, will be difficult. To enhance compliance with penicillin recommendations, all physicians responsible for care of patients must be devoted to educating patients. At each visit the surgeons, radiotherapist, and oncologist must persist in this educational effort.
PNEUMOCOCCAL VACCINATION The credit for the present use of pneumococcal vaccination belongs to Dr. Robert Austrian who has studied and carefully nurtured this preventive medicine concept for over 20 years. 3The present commercially available vaccine contains the capsular polysaccharides of 14 pneumococcal serotypes. These 14 types account for over 80 per cent of the serious pneumococcal infections encountered in man. The polysaccharides contained in this vaccine are highly purified and, as such, few side effects of vaccination are encountered aside from transient, mild local tenderness. Systemic reactions consisting of fever occur in 2 to 3 per cent of adults and less than 10 per cent of children. The antibody response of normal individuals to the vaccine has been excellent. Significant titers have developed for all 14 serotypes present. Antibody persists in elevated concentrations for at least three years after vaccination. 31 · 46 Other studies of response to pneumococcal vaccine responsiveness are currently in progress. We have observed that while the antibody responses of patients splenectomized for trauma or hereditary spherocytosis are
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similar for single antigens to nonsplenectomized controls, splenectomized patients respond to a fewer number of antigens in these polyvalent vaccinesY Several other caveats have been added to the seemingly excellent results obtained to date.' 5 The titer of pneumococcal antibody decreases over a period of a year or so after vaccine, and antibody to specific types has been noted to revert to prevaccination levels in less than six months. 5 Hopefully, an anamnestic response to the invading pneumococcus will provide appropriate antibody stimulus for protection or amelioration of infection, even though low amounts of specific antibody may be detectable at onset of infection. The safety and response of booster vaccination have been questioned owing to increased local and systemic reactions. 5 This data collection has just begun and will need extensive review before vaccination can be recommended as a substitute for antimicrobial prophylaxis. Cooperative clinical groups are studying both antibody response and clinical effect of pneumococcal vaccination immediately before or after splenectomy during staging laparotomy in patients with Hodgkin's disease. This subject will be reviewed separately in the near future. 17 Several studies have shown clinical benefit from use of pneumococcal vaccination. Austrian noted that pneumococcal vaccine was 82 per cent effective in preventing vaccine-type pneumococcal bacteremia, and there was no increase in the frequency of non vaccine pneumococcal types in this population. The duration of protection is unknown, though antibody persisted at 30 to 50 per cent of its peak value for two to three years in this study. 41 Children with sickle cell disease also have normal antibody response to pneumococcal vaccination.' Over two years following vaccination, none of 140 vaccinated patients had vaccine-type sepsis, whereas 8 of 106 nonvaccinated patients had vaccine-type pneumococcal bacteremia. Although these results are encouraging, at this time we conclude that there is insufficient clinical data to rely solely on pneumococcal vaccination as the only method for preventing overwhelming postsplenectomy infection in splenectomized patients.
MANAGEMENT OF SPLENIC TRAUMA Conservative surgical management of splenic trauma has become common in the past five years. 25 This quiet revolution has occurred mainly because of the threat of overwhelming postsplenectomy infection if splenectomy is performed. Heretofore, the suspicion of bleeding from a ruptured spleen was sufficient cause for laparotomy and splenectomy. But now several pediatric centers utilize careful observation as first policy in these cases. If there is clinical stability with regard to vital signs, abdominal findings, and hematocrit, some surgeons would continue clinical surveillance without operative intervention. 19 Laparotomy for many clinical reasons is still the prime diagnostic method to exclude ruptures of other organs such as liver and/or gut. There
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has been even a greater revolution in the concept of management of the ruptured spleen at the time of surgery. 8 • 22 • 37 Remodeling, mattress suturing, and repairing of rents and holes in spleen, which previously had been considered impossible, are now accepted procedures. 38 A new compound avetine has been recently marketed and shows promise of providing splenic hemostasis. 26 In our institution management of splenic tears includes a suture oflaceration with vicryl using pedicled omentum to fill the defect. If this initial effort fails to stop the bleeding, ligation of the main splenic artery can be accomplished, depending on the short gastrics for blood supply. The spleen is also wrapped circumferentially with vicryl suture in three areas to aid in tamponade. Radiologic diagnosis by scanning can be a guide for supplementation of clinical acumen in the difficult period of time before deciding whether or not to do a splenectomy. 42
SPLENOSIS Implantation by accident or by replacement of splenic tissue into the peritoneum of experimental animals results in growth of splenic tissue in situ, and is called "splenosis." Implanted splenic tissue regrows to a weight approximtely equal that of the original spleen. 44 In experimental animal studies, implantation of splenic tissue microscopically looks like real splenic tissue, and produces the "leukophilic 'Y globulin activity" and normal serum opsonic activity required for bactericidal action. 36 Pneumococcal challenge of experimental animals with splenosis resulted in a marked reduction of mortality in one study20 but had no benefit in another.'16 Clinicians have concerned themselves with the function of these implanted nodules of splenic tissue for the past 50 years. Pearson 29 has shown that there is functional "splenic activity" subsequent to splenectomy for trauma. This "splenosis," or heterotopic autotransplantation of splenic tissue at time of original injury, was documented in two ways. There was a failure to find Howell-Jolly bodies and "pitted red cells" in 13 of 20 patients. Also, in five children 99mTc sulfur colloid scan demonstrated multiple small nodules. This evidence clearly indicates that functional splenic activity may be more frequent following traumatic rupture of spleen than heretofore suspected. The suggestion that such autotransplants may be therapeutic in preventing infection3• 29 is of great interest. Clearly the surgical guidelines outlined for conservative management of possible splenic trauma in the above sections will provide greater time for study of "heterotopic autotransplants." Furthermore, partial splenectomy may provide for pneumococcal clearance as noted in experimental animals. 10 The "splenotic tissues" recorded in literature obviously lack the vasculature and thus functional clearance of a flow of 250 liters of blood daily seen in the normal spleen. Future studies of patients with "splenosis" should include measurement of immunoglobulins (i.e., IgM), clearance rate of particulate antigens (i.e., 131I aggregated albmnin), and
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production ofheterophilic antibodies to intravenous challenge of antigens such as bacteriophage Ox 14 7 (as noted above). Finally, until there are enough "splenotic" patients to provide clinical assurance of failure to develop overwhelming postsplenectomy infection, we recommend penicillin prophylaxis and pneumococcal vaccine for individual patients. The reporting of a single case of overwhelming postsplenectomy infection with such a "functional spleen" will be of invaluable clinical significance.
CONCLUSION Overwhelming postsplenectomy infection is now a recognized and clinically accepted entity. The rapidity of onset and high mortality make treatment of overwhelming postsplenectomy infection an emergency of highest priority. The incidence of overwhelming postsplenectomy infection varies from 1.45 per cent when splenectomy is done for trauma upward to 20 per cent in thalassemia and treated Hodgkin's disease. There are cases of overwhelming postsplenectomy infection in adults many years post splenectomy. Individual analyses searching for "functional splenic activity" in traumatic cases is recommended. Careful documentation of normal hematologic findings (i.e., Howell-Jolly bodies), normal IgM, and normal particulate clearance should be obtained. All splenectomized patients should receive daily penicillin prophylaxis and pneumococcal vaccination. The risk of death from overwhelming postsplenectomy infection is enough of a threat to assure patient compliance. Careful preoperative thought as to the absolute need for splenectomy, vis-a-vis clinical condition, must be weighed against the lifetime possibility of potential development of overwhelming postsplenectomy infection.
REFERENCES 1. Amman, A., Addiego, I., and Wara, D. W.: Pneumococcal immunization in sickle cell anemia and asplenia. New Engl. J. Med., 297:897, 1977. 2. Anderson, V., Cohn, J., and S!i!renson, S. F.: Immunological studies in children before and after splenectomy. Acta Paediat. Scand., 65:409, 1976. 3. Austrian, R.: Random gleanings from a life with the pneumococcus, J. Infect. Dis., 131:474, 1975. 4. Balfanz, J. R., Nesbit, M. E., Jarvis, C., et al.: Overwhelming sepsis following splenectomy for trauma. J. Pediat., 88:458, 1976. 5. Borgono, J. M., McLean, A. A., and Vella, P. P.: Vaccination and revaccination with polyvalent pneumococcal polysaccharide vaccines in adults and infants. Proc. Soc. Exp. Bioi. Med., 157:148, 1978. 6. Carlisle, H. N., and Saslaw, S.: Properdin levels in splenectomized persons. Proc. Soc. Exp. Bioi. Med., 102:150, 1959. 7. Chilcote, R. R., Baehner, R. L., and Hammond, D.: Septicemia and meningitis in children splenectomized for Hodgkin's disease. New Engl. J. Med., 295:198, 1976. 8. Douglas, G. D., and Simpson, J. S.: Conservative management of splenic trauma. J. Pediat. Surg., 6:565, 1971. 9. Fine, D. P.: Pneumococcal type associated variability in alternate complement pathway activation. Infect. Immun., 12:772, 1975.
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10. Fleming, C. R., Dickson, E. R., and Harrison, E. G., Jr.: Splenosis: Autotransplantation of splenic tissue. Am. J. Med., 61:414, 1976. 11. Giebink, G. S., Foker, J. E., Thomas, P. J., et al.: Serum opsonic activity and aru;onic response to pneumococcal vaccination in splenectomized children. Pediat. Res., 12:480, 1978. . 12. Giebink, G. S., Verhoff. J., Peterson, P. K., et al.: Opsonic requirementsforphagocytosisof Streptococcus pneumoniae. Types VI, XVIII, XXIII and XXV. Infect. Immun., 18:291, 1977. 13. Jacob, H. S.: Born again to work again (editoral). New Engl. J. Med., 298:1415, 1978. 14. King, H., and Schumacher, H. B., Jr.: Splenic studies. I. Susceptibility to infection after splenectomy performed in infancy. Am. Surg., 136:239, 1952. 15. Klein, J. 0., and Mortimer, E. A.: Use of pneumococcal vaccine in children. Pediatrics, 61 :321, 1978. 16. Krivit, W.: Overwhelming post splenectomy infection. Am. J. Hematol., 2:193, 1977. 17. Krivit, W., Giebink, S. G., and Leonard, A.: Hodgkin's disease in children. Progr. Hematol. Oncol., submitted for publication. 18. Lanzkowsky, P., Karayalcin, G., and Shende, A.: Complications of laparotomy and splenectomy in stages of Hodgkin's disease in children. Am. J. Hematol., 1:393, 1976. 19. Lanzkowsky, P., Lynn, H., Hendren, W. H., et al.: Newmethodofrepairofsplenictrauma in order to prevent splenectomy. Pediat. News, March, 1976. 20. Likhite, V. V.: Protection against fulminant sepsis in splenectomized mice by implantation of autochthonous splenic tissue. Exp. Hematol., 6:433, 1978. 21. Lucas, R. V., and Krivit, W.: Overwhelming infection in children following splenectomy. J. Pediat., 57:185, 1960. 22. Lynn, H. B.: A re-evaluation of splenectomy. Pediat. Ann., 5:12, 1976. · 23. Matas, A. J., Simmons, R. L., Buselmeier, T. J., et al.: Lethal complications of bilateral nephrectomy and splenectomy in hemodialyzed patients. Am. J. Surg., 129:616, 1975. 24. Mondorf, W., Lennert, K. A., and Kollmar, M.: Quantitative immunoglobulin best immunogen post traumatisch splenechtomierten. Klin. Wochenschr., 47:533, 1969. 25. Morgenstern, L.: The avoidable complicati
Overwhelming Postsplenectomy Infection William Krivit, M.D., Ph.D.,'~ G. Scott Giebink, M.D., t and Arnold Leonard, M.D., Ph.D. t
Splenectomy done at any age and for any reason increases the risk for death due to overwhelming bacterial infection. Postsplenectomy infection has a rapid onset and a mortality rate of 50 per cent that distinguishes it from other bacterial infections. The immune aberration following splenectomy includes decreased serum lgM levels, altered serum opsonic function, and failure to respond to intravenous particulate antigen challenge. The risk for overwhelming postsplenectomy infection in individuals splenectomized for trauma is 50-fold greater than for the normal population and is considerably greater following splenectomy for idiopathic thrombocytopenia, acquired hemolytic anemia, Hodgkin's disease, and other hematologic disorders. The first step in preventing overwhelming postsplenectomy infection is to review surgical indications for splenectomy so that the conservative management of patient's disease will be heavily considered. Included in the surgical armamentarium should be techniques of splenic repair in cases of trauma, awareness of the syndrome of overwhelming postsplenectomy infection and need of penicillin prophylaxis and pneumococcal vaccination. Autosplenic transplantation (splenosis) has been suggested as a method for providing intrinsic spleen tissue, which can prevent overwhelming postsplenectomy infection. However, clinical proof ofthe effectiveness of splenosis is still lacking. The syndrome of overwhelming postsplenectomy infection has become well identified and accepted within the past few years. One of the major reasons for this change has been the extensive review by Singer in 1973. 39 His collection of data clearly gave form and substance to a unique syndrome. An update of this material by Krivit in 1977 summarized the immunologic data relating to lgM deficiency following splenectomy. 16 '''Professor of Pediatrics, University of Minnesota Medical School and Hospitals, Minneapolis, Minnesota t Assistant Professor, Department of Pediatrics, University of Minnesota Medical School and Hospitals, Minneapolis, Minnesota ~Professor, Department of Surgery, and Head, Division of Pediatric Surgery, University of Minnesota Medical School and Hospitals, Minneapolis, Minnesota Supported by grants Al-08821, CA-21737, and HL-07145, from the National Institute of Health.
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The use of splenectomy as a therapeutic measure rests in surgeons' hands. This article addresses the problems and potential solutions tha~ face the surgeon. Indeed, this is most appropriate since surgeons have been in the forefront of research on overwhelming postsplenectomy infection. Morris and Bullock in 1919 were first to predict that removal of the spleen would result in an increased susceptibility to infection. 27 King and Schumacher in 1952 stimulated interest of many concerning overwhelming postsplenectomy infection in patients with hereditary spherocytosis. 14 In 1957 Smith presented his data on postsplenectomy infection in patients with thalassemia. 40 Our experience and later review at the University of Minnesota were the first to support Smith's conclusions. 21
CLINICAL CHARACTERISTICS Description of Syndrome The characteristic events in overwhelming postsplenectomy infection are the sudden onset of nausea, vomiting, and confusion leading to coma, and often proceeding to death within hours. The case fatality rate is 50 to 75 per cent in all series studied. The infecting organism most often recovered from patients with overwhelming postsplenectomy infection is S. pneumoniae. In decreasing frequency, N. meningitidis, E. coli, H. in:fluenzae, and S. aureus are found. Virus infection was noted in the original description of overwhelming postsplenectomy infection. Evidence of disseminated intravascular coagulation, severe hypoglycemia, electrolyte imbalance, and shock are frequently noted. Diplococci are often seen on peripheral blood smears in patients with overwhelming postsplenectomy infection. Blood cultures frequently yield 106 bacteria per ml of blood, a concentration far in excess of the bacteremia that accompanies pneumonia and other ordinary infections. 45 At autopsy, the observations are typical for septicemia but also include adrenal hemorrhage (Waterhouse-Friderichsen syndrome) in a high proportion of cases. Therapy, therefore, must be vigorous with immediate and intensive antibiotic usage, and extensive supportive fluid and electrolyte management. Traumatic Rupture of Spleen The patient who undergoes splenectomy because of abdominal trauma serves as the prototype for this discussion because these patients have no underlying immunologic or hematologic disease. Sufficient reports of overwhelming postsplenectomy infection subsequent to trauma provide appropriate data to make this a significant concern for surgeons. Our report 4 and those of others have been summarized. 16 At least 21 individuals have been enumerated in the literature who have had overwhelming postsplenectomy infection following splenectomy for trauma. Their ages ranged from 7 to 50 years at the time of infection. The interval between splenectomy and infection ranged from 7 months to 25 years. Case fatality was 67 per cent. To establish the true risk of patients developing overwhelming postsplenectomy infection requires knowledge of the incidence of severe
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bacterial infections in a normal nonsplenectomized population. The baseline data for normal individuals was obtained from comprehensive epidemiologic health survey in Newcastle-Upon-Tyne, England. In this survey, 84 7 children were followed during the first five years oflife; 0. 7 per cent had bacterial meningitis or sepsis during the observation period. 39 Mortality owing to sepsis was 0.01 per cent. The incidence of overwhelming postsplenectomy infection following splenectomy for trauma is 10 of 688 or 1.45 per cent, and mortality owing to sepsis is 0.58 per cent. 39 Statistical considerations are important in understanding the risk of splenectomized patients. Many surgeons have seen overwhelming postsplenectomy infection and are convinced of its validity. Others have splenectomized patients without ever seeing overwhelming postsplenectomy infection. The latter circumstance is not surprising since the overall incidence of overwhelming postsplenectomy infection is relatively low. It would be anticipated that within small series of splenectomized patients, no cases of overwhelming postsplenectomy infection would be seen; but to conclude that splenectomy does not result in an increased risk of overwhelming postsplenectomy infection after reviewing, for example, 60 patients is statistically unwarranted. The conclusion here is that the overall incidence of overwhelming postsplenectomy infection in patients splenectomized for trauma must carry more weight than the small negative series. Fortunately, more centers have carefully reviewed their splenectomized patients, and there is increasing general agreement regarding the reality of overwhelming postsplenectomy infection subsequent to splenectomy at any age and for any disease.
Hereditary Spherocytosis The immune system in hereditary spherocytosis is normal, and there is minimal reticuloendothelial system disease from hemolysis. To date, overwhelming postsplenectomy infection has not been reported in a nonsplenectomized individual with hereditary spherocytosis. Yet, numerous instances of overwhelming postsplenectomy infection have been reported following splenectomy for this condition. The syndrome of overwhelming postsplenectomy infection has been documented in 3. 5 per cent of children splenectomized for hereditary spherocytosis. 39 Schilling reported an overwhelming postsplenectomy infection in one child. 34 Adults splenectomized for hereditary spherocytosis also die from overwhelming postsplenectomy infection. 32 Hodgkin's Disease With the modern technique of staging Hodgkin's disease by laparotomy and splenectomy and with the increased use of chemotherapy and radiation, the syndrome of overwhelming postsplenectomy infection has been observed. It is not known whether this sudden surge of an hitherto unrecognized complication of Hodgkin's disease is owing to splenectomy or to chemotherapy and radiation treatment for the disease. Chilcote reviewed 200 children and young adolescents with Hodgkin's disease for Children's Cancer Study Group. 7 The incidence of overwhelming postsplenectomy infection was 10 per cent with an overall mortality of
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5 per cent. Subsequently, in the several centers in which penicillin prophylaxis· has been instituted, overwhelming postsplenectomy infection has not occurred despite continuation of prior therapeutic maneuvers. This suggests that splenectomy and not radiation or chemotherapy is the cause of overwhelming postsplenectomy infection in Hodgkin's disease, s-ince treatment is essentially identical to that before the use of penicillin. A review of the problems concerning splenectomy in Hodgkin's disease is forthcoming. 17
Renal Transplant At the University of Minnesota, splenectomy at the time of bilateral nephrectomy had been done in order to increase immunologic acceptance of renal transplant. Four children with severe pneumococcal infections have been reported in a population of approximately 120 children under the age of 16 who had undergone transplantation. Two had severe meningitis, one had septic arthritis, and one succumbed to overwhelming pneumococcal sepsis. 23 At present, because of these circumstances, penicillin prophylaxis is now being used in all splenectomized children. Another series has also been reported, indicating occurrence of overwhelming postsplenectomy infection in siinilar situations. 35 Other Clinical Conditions Patients with sickle cell anemia are quite susceptible to overwhelming postsplenectomy infection because of autosplenectomy intrinsic to the basic disease process. Congenital asplenia is easily diagnosed because of characteristic heart disease and the presence of Howell-Jolly bodies. This hematologic finding is always found post splenectomy if there is a complete removal of all splenic tissue. Statistical considerations regarding the syndrome of overwhelming postsplenectomy infection in these two conditions are similar to those in surgical splenectomy. In addition, there are numerous instances of overwhelming postsplenectomy infection in patients who have underlying disturbance of the reticuloendothelial system. IMMUNOLOGIC ASPECTS OF SPLENECTOMY Humoral Immune Function Several lines of evidence suggest that the splenectomized host has compromised humoral defenses. Both immunoglobulin and complement deficiencies have been reported in these patients. Immunoglobulins Antibody response to intravenously administered particulate antigens is reduced post splenectomy. Splenectomized humans did not form hemolysin antibody to intravenously administered sheep red blood cells. 33 Antibody responses to primary intravenous immunization with a bacteriophage 8 x 174 is decreased despite normal clearance of these particulate antigens. 43 This observation suggests that the nonsplenic por-
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tion of the reticuloendothelial system adequately compensates mechanically for the loss of the spleen, but that antibody formation in these nonsplenic sites is less efficient than in the spleen. Asplenic individuals also were shown in this report to have an inability to switch from IgM to IgG antibody production. In every series reported, the average serum IgM level in splenectomized patients is significantly depressed below the normal range. 16 That the IgM depression is owing to the splenectomy and not to the underlying disease process is best exemplified in traumatic rupture of the spleen. In adults, the average and standard deviation oflgMlevelin splenectomized group was 94 ± 48 (n = 22) as compared with 159 ± 74 (n = 67) in agematched non splenectomized controls. 24 In another study in children, the IgM level post splenectomy for traumatic rupture of spleen was 58.7 ± 31.0 (n = 31) compared with 93.4 ± 46.8 in normal children of all ages. 16 IgG and IgA immunoglobulins frequently are either elevated or normal in splenectomized patients. 16 The pattern of immunoglobulin concentration is unrelated to the depression oflgM. Limited data collected to date on IgD have not revealed any specific deficiencies, and only a few reports of IgE levels are noted. Host defense against most pathogenic bacteria involves opsonization, a serum function requiring antibody and complement, for efficient phagocytosis to occur. Although antibody alone can be opsonic for some organisms, opsonization is markedly enhanced by complement. 12 Since most pneumococci are efficiently opsonized via the alternative complement pathway, 9 • 12 and because type-specific antibody may not be required for activating this pathway, the alternative pathway may represent the principal mechanism for pneumococcal opsonization in the nonimmune host. Accordingly, complement deficiencies might seriously impair opsonization and reduce host resistance to invading pneumococci. Carlisle and Saslaw 6 were the first to report diminished properedin activity, an altemative complement pathway factor, in asplenic humans. Polhill and Johnston 30 observed significantly reduced alternative complement pathway function in about 20 per cent of asplenic humans. Depressed complement function is not universal in these patients since others have found normal levels of complement in asplenic patients. The net effect of impaired antibody formation and of complement dysfunction may reduce serum opsonic activity in some patients. However, Winkelstein et alY and Giebink et al." were unable to show diminished serum opsonic activity for several pneumococcal types in asplenic patients. However, after subcutaneous immunization with pneumococcal vaccine, asplenic patients failed to increase their serum pneumococcal opsonic activity in concordance with increased antibody levels! Normal control patients showed concordance between antibody and opsonic levels.
Cellular Immune Function The number of circulating T lymphocytes is somewhat reduced following splenectomy. 2 • 34 Lymphocyte mitogen proliferative response was
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decreased for a period of time and then became normal. Polymorphonuclear leukocyte functions and C3 levels were not changed in asplenic patients.34
PENICILLIN (ANTIBIOTIC) PROPHYLAXIS Because overwhelming postsplenectomy infection is caused by pneumococci in 50 per cent of cases, penicillin prophylaxis has been successful in effectively reducing the incidence. Lanzkowsky demonstrated that penicillin prophylaxis eradicated the syndrome of overwhelming postsplenectomy infection in his institution, whereas the incidence before penicillin usage was 5 per cent. 18 Two patients who were not taking prescribed penicillin succumbed to overwhelming postsplenectomy infection. In another review, overwhelming postsplenectomy infection occurred in 10 per cent of children who underwent laparotomy and splenectomy for Hodgkin's disease with an associated mortality of 5 per cent. 7 Overwhelming postsplenectomy infection was not found in any of the member institutions using penicillin prophylaxis for all their patients with Hodgkin's disease. Subsequently, many more institutions began utilizing penicillin prophylaxis, and in a recent informal review, none of the polled physicians had observed cases of overwhelming postsplenectomy infection. Compliance for daily penicillin ingestion for 5 to 10 years, if not for life, will be difficult. To enhance compliance with penicillin recommendations, all physicians responsible for care of patients must be devoted to educating patients. At each visit the surgeons, radiotherapist, and oncologist must persist in this educational effort.
PNEUMOCOCCAL VACCINATION The credit for the present use of pneumococcal vaccination belongs to Dr. Robert Austrian who has studied and carefully nurtured this preventive medicine concept for over 20 years. 3The present commercially available vaccine contains the capsular polysaccharides of 14 pneumococcal serotypes. These 14 types account for over 80 per cent of the serious pneumococcal infections encountered in man. The polysaccharides contained in this vaccine are highly purified and, as such, few side effects of vaccination are encountered aside from transient, mild local tenderness. Systemic reactions consisting of fever occur in 2 to 3 per cent of adults and less than 10 per cent of children. The antibody response of normal individuals to the vaccine has been excellent. Significant titers have developed for all 14 serotypes present. Antibody persists in elevated concentrations for at least three years after vaccination. 31 · 46 Other studies of response to pneumococcal vaccine responsiveness are currently in progress. We have observed that while the antibody responses of patients splenectomized for trauma or hereditary spherocytosis are
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similar for single antigens to nonsplenectomized controls, splenectomized patients respond to a fewer number of antigens in these polyvalent vaccinesY Several other caveats have been added to the seemingly excellent results obtained to date.' 5 The titer of pneumococcal antibody decreases over a period of a year or so after vaccine, and antibody to specific types has been noted to revert to prevaccination levels in less than six months. 5 Hopefully, an anamnestic response to the invading pneumococcus will provide appropriate antibody stimulus for protection or amelioration of infection, even though low amounts of specific antibody may be detectable at onset of infection. The safety and response of booster vaccination have been questioned owing to increased local and systemic reactions. 5 This data collection has just begun and will need extensive review before vaccination can be recommended as a substitute for antimicrobial prophylaxis. Cooperative clinical groups are studying both antibody response and clinical effect of pneumococcal vaccination immediately before or after splenectomy during staging laparotomy in patients with Hodgkin's disease. This subject will be reviewed separately in the near future. 17 Several studies have shown clinical benefit from use of pneumococcal vaccination. Austrian noted that pneumococcal vaccine was 82 per cent effective in preventing vaccine-type pneumococcal bacteremia, and there was no increase in the frequency of non vaccine pneumococcal types in this population. The duration of protection is unknown, though antibody persisted at 30 to 50 per cent of its peak value for two to three years in this study. 41 Children with sickle cell disease also have normal antibody response to pneumococcal vaccination.' Over two years following vaccination, none of 140 vaccinated patients had vaccine-type sepsis, whereas 8 of 106 nonvaccinated patients had vaccine-type pneumococcal bacteremia. Although these results are encouraging, at this time we conclude that there is insufficient clinical data to rely solely on pneumococcal vaccination as the only method for preventing overwhelming postsplenectomy infection in splenectomized patients.
MANAGEMENT OF SPLENIC TRAUMA Conservative surgical management of splenic trauma has become common in the past five years. 25 This quiet revolution has occurred mainly because of the threat of overwhelming postsplenectomy infection if splenectomy is performed. Heretofore, the suspicion of bleeding from a ruptured spleen was sufficient cause for laparotomy and splenectomy. But now several pediatric centers utilize careful observation as first policy in these cases. If there is clinical stability with regard to vital signs, abdominal findings, and hematocrit, some surgeons would continue clinical surveillance without operative intervention. 19 Laparotomy for many clinical reasons is still the prime diagnostic method to exclude ruptures of other organs such as liver and/or gut. There
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has been even a greater revolution in the concept of management of the ruptured spleen at the time of surgery. 8 • 22 • 37 Remodeling, mattress suturing, and repairing of rents and holes in spleen, which previously had been considered impossible, are now accepted procedures. 38 A new compound avetine has been recently marketed and shows promise of providing splenic hemostasis. 26 In our institution management of splenic tears includes a suture oflaceration with vicryl using pedicled omentum to fill the defect. If this initial effort fails to stop the bleeding, ligation of the main splenic artery can be accomplished, depending on the short gastrics for blood supply. The spleen is also wrapped circumferentially with vicryl suture in three areas to aid in tamponade. Radiologic diagnosis by scanning can be a guide for supplementation of clinical acumen in the difficult period of time before deciding whether or not to do a splenectomy. 42
SPLENOSIS Implantation by accident or by replacement of splenic tissue into the peritoneum of experimental animals results in growth of splenic tissue in situ, and is called "splenosis." Implanted splenic tissue regrows to a weight approximtely equal that of the original spleen. 44 In experimental animal studies, implantation of splenic tissue microscopically looks like real splenic tissue, and produces the "leukophilic 'Y globulin activity" and normal serum opsonic activity required for bactericidal action. 36 Pneumococcal challenge of experimental animals with splenosis resulted in a marked reduction of mortality in one study20 but had no benefit in another.'16 Clinicians have concerned themselves with the function of these implanted nodules of splenic tissue for the past 50 years. Pearson 29 has shown that there is functional "splenic activity" subsequent to splenectomy for trauma. This "splenosis," or heterotopic autotransplantation of splenic tissue at time of original injury, was documented in two ways. There was a failure to find Howell-Jolly bodies and "pitted red cells" in 13 of 20 patients. Also, in five children 99mTc sulfur colloid scan demonstrated multiple small nodules. This evidence clearly indicates that functional splenic activity may be more frequent following traumatic rupture of spleen than heretofore suspected. The suggestion that such autotransplants may be therapeutic in preventing infection3• 29 is of great interest. Clearly the surgical guidelines outlined for conservative management of possible splenic trauma in the above sections will provide greater time for study of "heterotopic autotransplants." Furthermore, partial splenectomy may provide for pneumococcal clearance as noted in experimental animals. 10 The "splenotic tissues" recorded in literature obviously lack the vasculature and thus functional clearance of a flow of 250 liters of blood daily seen in the normal spleen. Future studies of patients with "splenosis" should include measurement of immunoglobulins (i.e., IgM), clearance rate of particulate antigens (i.e., 131I aggregated albmnin), and
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production ofheterophilic antibodies to intravenous challenge of antigens such as bacteriophage Ox 14 7 (as noted above). Finally, until there are enough "splenotic" patients to provide clinical assurance of failure to develop overwhelming postsplenectomy infection, we recommend penicillin prophylaxis and pneumococcal vaccine for individual patients. The reporting of a single case of overwhelming postsplenectomy infection with such a "functional spleen" will be of invaluable clinical significance.
CONCLUSION Overwhelming postsplenectomy infection is now a recognized and clinically accepted entity. The rapidity of onset and high mortality make treatment of overwhelming postsplenectomy infection an emergency of highest priority. The incidence of overwhelming postsplenectomy infection varies from 1.45 per cent when splenectomy is done for trauma upward to 20 per cent in thalassemia and treated Hodgkin's disease. There are cases of overwhelming postsplenectomy infection in adults many years post splenectomy. Individual analyses searching for "functional splenic activity" in traumatic cases is recommended. Careful documentation of normal hematologic findings (i.e., Howell-Jolly bodies), normal IgM, and normal particulate clearance should be obtained. All splenectomized patients should receive daily penicillin prophylaxis and pneumococcal vaccination. The risk of death from overwhelming postsplenectomy infection is enough of a threat to assure patient compliance. Careful preoperative thought as to the absolute need for splenectomy, vis-a-vis clinical condition, must be weighed against the lifetime possibility of potential development of overwhelming postsplenectomy infection.
REFERENCES 1. Amman, A., Addiego, I., and Wara, D. W.: Pneumococcal immunization in sickle cell anemia and asplenia. New Engl. J. Med., 297:897, 1977. 2. Anderson, V., Cohn, J., and S!i!renson, S. F.: Immunological studies in children before and after splenectomy. Acta Paediat. Scand., 65:409, 1976. 3. Austrian, R.: Random gleanings from a life with the pneumococcus, J. Infect. Dis., 131:474, 1975. 4. Balfanz, J. R., Nesbit, M. E., Jarvis, C., et al.: Overwhelming sepsis following splenectomy for trauma. J. Pediat., 88:458, 1976. 5. Borgono, J. M., McLean, A. A., and Vella, P. P.: Vaccination and revaccination with polyvalent pneumococcal polysaccharide vaccines in adults and infants. Proc. Soc. Exp. Bioi. Med., 157:148, 1978. 6. Carlisle, H. N., and Saslaw, S.: Properdin levels in splenectomized persons. Proc. Soc. Exp. Bioi. Med., 102:150, 1959. 7. Chilcote, R. R., Baehner, R. L., and Hammond, D.: Septicemia and meningitis in children splenectomized for Hodgkin's disease. New Engl. J. Med., 295:198, 1976. 8. Douglas, G. D., and Simpson, J. S.: Conservative management of splenic trauma. J. Pediat. Surg., 6:565, 1971. 9. Fine, D. P.: Pneumococcal type associated variability in alternate complement pathway activation. Infect. Immun., 12:772, 1975.
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10. Fleming, C. R., Dickson, E. R., and Harrison, E. G., Jr.: Splenosis: Autotransplantation of splenic tissue. Am. J. Med., 61:414, 1976. 11. Giebink, G. S., Foker, J. E., Thomas, P. J., et al.: Serum opsonic activity and aru;onic response to pneumococcal vaccination in splenectomized children. Pediat. Res., 12:480, 1978. . 12. Giebink, G. S., Verhoff. J., Peterson, P. K., et al.: Opsonic requirementsforphagocytosisof Streptococcus pneumoniae. Types VI, XVIII, XXIII and XXV. Infect. Immun., 18:291, 1977. 13. Jacob, H. S.: Born again to work again (editoral). New Engl. J. Med., 298:1415, 1978. 14. King, H., and Schumacher, H. B., Jr.: Splenic studies. I. Susceptibility to infection after splenectomy performed in infancy. Am. Surg., 136:239, 1952. 15. Klein, J. 0., and Mortimer, E. A.: Use of pneumococcal vaccine in children. Pediatrics, 61 :321, 1978. 16. Krivit, W.: Overwhelming post splenectomy infection. Am. J. Hematol., 2:193, 1977. 17. Krivit, W., Giebink, S. G., and Leonard, A.: Hodgkin's disease in children. Progr. Hematol. Oncol., submitted for publication. 18. Lanzkowsky, P., Karayalcin, G., and Shende, A.: Complications of laparotomy and splenectomy in stages of Hodgkin's disease in children. Am. J. Hematol., 1:393, 1976. 19. Lanzkowsky, P., Lynn, H., Hendren, W. H., et al.: Newmethodofrepairofsplenictrauma in order to prevent splenectomy. Pediat. News, March, 1976. 20. Likhite, V. V.: Protection against fulminant sepsis in splenectomized mice by implantation of autochthonous splenic tissue. Exp. Hematol., 6:433, 1978. 21. Lucas, R. V., and Krivit, W.: Overwhelming infection in children following splenectomy. J. Pediat., 57:185, 1960. 22. Lynn, H. B.: A re-evaluation of splenectomy. Pediat. Ann., 5:12, 1976. · 23. Matas, A. J., Simmons, R. L., Buselmeier, T. J., et al.: Lethal complications of bilateral nephrectomy and splenectomy in hemodialyzed patients. Am. J. Surg., 129:616, 1975. 24. Mondorf, W., Lennert, K. A., and Kollmar, M.: Quantitative immunoglobulin best immunogen post traumatisch splenechtomierten. Klin. Wochenschr., 47:533, 1969. 25. Morgenstern, L.: The avoidable complicati
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