REVIEW

Splenic Function: Normal, Too Much and Too Little

EDWARD R. EICHNER, M.D. Okluhoma City, Oklahomu

This review is concerned with normal splenic function, mechanisms and consequences of splenomegaly, hypersplenism, the medical indications for splenectomy and the various aspects of hyposplenism. The potential problem of lethal septicemia in hyposplenic or asplenic patients is also considered. Recent research indicates that the spleen has unique and vita! functions. Our knowledge of normal and abnormal splenic function has now been expanded considerably. Although the term hypersplenism has been used for 70 years, its definition is imprecise and its mechanisms are diverse. Also, the many aspects and clinical importance of hyposplenism, a potentially lethal condition, need emphasis. In this article I will review the normal functions of the spleen and the diverse aspects of hypersplenism and hyposplenism. SPLENIC PUNCTION

From the Hematology-Oncology Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Requests for reprints should be addressed to Dr. Edward R. Eichner. Section of Hematology-Oncology, University of Oklahoma Health Sciences Center. P.O. Box 26961. Oklahoma City, Oklahoma 73190. Manuscript accepted September 27.1976.

The spleen is a critical line of defense when the host is invaded by blood-borne bacteria to which he has little or no preexisting antibody. The unique splenic circulation makes it the main site of clearance of such microorganisms and the initial site of synthesis of specific immunoglobulin M (IgM) antibody [l-5]. Animal studies with intravenous, radiolabeled Salmonella, Escherichia coli and pneumococci have shown that the liver clears the bulk of well-opsonized bacteria from the blood but that the spleen, a more efficient filter, is more effective in removing poorly opsonized bacteria 16).When no specific antibody is present to permit efficient liver uptake, clearance of blood-borne bacteria is delayed and is dependent on splenic function. A recent novel experiment in rabbits with plastic microspheres too large to pass through the pores in the venous sinuses has proved the fundamental anatomic point underlying the singular splenic microcirculation: only 10 per cent of the blood in the arterial capillaries is emptied directly into venous sinuses. Ninety per cent of the blood entering the spleen empties into the “open circulation” of the red pulp, and the blood is then forced into the sinuses [2]. This means that the blood cells and other particles contained in the blood are required to circulate along the fine meshwork of the splenic cords until they can squeeze through tiny 0.5 to 2.5 wrn pores between endothelial cells lining the walls of the venous sinuses [7] to enter the venous circulation and leave the spleen. This delayed microcirculation allows time for splenic phagocytes to remove even poorly opsonized bacteria. The unique microcirculation of the spleen also facilitates immune response to intravenously administered particulate antigens. When blood enters the spleen, the soluble antigens are skimmed off with much of the plasma to enter the right-angled arterioles supplying the

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TABLE I

Biologic Substances Removed by the Spleen ‘In normal subjects Red blood cell membrane Red blood cell surface pits and craters HowellJolly bodies Heinz bodies Pappenhelmer bodies Acanthocytes Senescent red blood cells In those with diseases Spherocytes (hereditary spherocytosis) Sickled cells, hemoglobin C cells Antibody-coated red blood CellS Antibody-coated platelets Antibody-coated white blood Cells

germinal centers of the white pulp, but the particulate antigens, such as tagged Salmonella flagellar antigens, lodge first in the red pulp and within hours are transported, possibly by mobile macrophages, across the marginal zone into the germinal center where IgM antibody response is initiated [3]. When the splenic microcirculation is impaired, as in sickle cell anemia, or when the spleen has been removed, the antibody response to blood-borne antigen is blunted, and serum IgM levels fall [4,8-lo]. The spleen is also a major site of synthesis of tuftsin and properdin, two proteins which serve as opsonins. Serum levels of tuftsin, a basic tetrapeptide that coats blood polymorphonuclear leukocytes to promote phagocytosis, are subnormal after splenectomy [ll,l2]. Serum levels of properdin, a vital component of the alternate pathway of complement activation, are also subnormal after splenectomy [x3]. Children with sickle cell anemia have subnormal levels of properdin and impaired alternate pathway activity. This impairs their serum opsonization of pneumococci and, along with their functional asplenia, puts them at risk for fatal pneumococcemia [l4-191. However, after undergoing splenectomy for trauma, normal children have normal pneumococcal serum opsonizing activity [20]. Although partial deficiencies of tuftsin and properdin may be minor risk factors after splenectomy or with functional asplenia, it seems likely that the integrity of the microcirculation of the spleen is crucial to the survival of the nonimmune patient with pneumococcemia. The spleen also carries out hematopoiesis in utero. In a classic example of the dictum that ontogeny recapitulates phylogeny, the human fetus produces blood cells in numerous extramedullary sites, sites which in lower vertebrates remain the organs of hematopoiesis. At five months, however, the human switches to strictly medullary hematopoiesis and discontinues synthesis in extramedullary locations, presumably because the microenvironment (“soil”) changes. However, these sites

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of embryonic hematopoiesis become active again in the poorly understood agnogenic myeloid metaplasia. This disorder comprises a heterogeneous group of entities which have in common histologic evidence of extramedullary hematopoiesis, especially in the spleen. This extramedullary hematopoiesis may be compensatory, neoplastic or even “myelostimulatory” in origin; it is not entirely normal but is characterized by ineffective hematopoiesis and abnormal erythrocyte morphology

Pll.

The sophisticated splenic filter, which receives 5 per cent of the blood volume per minute, makes the spleen a “training camp” for reticulocytes. Reticulocytes, which have excessive membrane and a weak negative surface charge, are preferentially retained by the spleen [22]. During their sojourn in the spleen, these cells are molded, pitted and, if abnormal, culled out (Table I). The spleen reduces the membrane surface area by one third, which converts red cells from targets into biconcave discs. In the process it removes a yet unidentified high molecular weight surface protein complex [23].The spleen also removes surface craters [24], pits from normal red cells any Howell-Jolly bodies (nuclear remnants], Heinz bodies (denatured hemoglobin] or Pappenheimer bodies (iron granules), and removes any acanthocytes (spur cells] that may be present [22,25].The new red cells, now free of debris, are then released from the spleen possessing the necessary deformability to circulate in the microvasculature for four months. At the end of this time, the senescent cells have lost enzymatic activity and membrane plasticity, so they are trapped and are destroyed in the spleen. These normal splenic functions enable it to remove abnormal blood cells (Table I). The spherocytes of hereditary spherocytosis are unable to pass through the spleen. Likewise, fixed sickled cells and hemoglobin C cells are too rigid to pass through the splenic pores. Any blood cell coated with immunoglobulin G (IgG) antibody is attacked and often destroyed by the spleen because the splenic monocytes have surface receptors for the Fc fragment of the IgG coating the blood cell [26]. Some of these IgG-coated cells escape as spherocytes, only to be destroyed in a subsequent circulation through the spleen. For this reason, the spleen is the predominant organ of cell destruction in autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura and probably in Felty’s syndrome. Finally, the spleen is also able to pit parasites, such as the malarial organism, from red blood cells 1271. APPROACH TO SPLENOMEGALY Palpable spleens are not always abnormal, and hypersplenic spleens are not always palpable. Patients with emphysema and low diaphragms commonly have palpable spleens. One study showed that 63 (3 per cent) of 2,200 healthy college freshmen had paIpable spleens [28], and a more recent study showed that almost 5 per

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cent of the hospital patients with normal spleens by scan were thought to have palpable spleens by their physicians [29]. In contrast, clinical splenomegaly is rarely noted in idiopathic (autoimmune] thrombocytopenic purpura, despite avid destruction of antibody-coated platelets by the spleen. Mild splenomegaly occurs with many diseases. It is not useful to list these. It is more productive to consider the mechanisms of splenomegaly and then the relatively few diseases which cause either giant splenomegaly (10 times or more its usual weight of about 200 g) or hypersplenism. Table II presents six mechanisms of splenomegaly and gives examples of common diseases in each category. The most common cause of splenomegaly is “work hypertrophy” from immune response and/or red blood cell destruction. Cirrhosis and splenic vein thrombosis produce splenomegaly by venous congestion. In the myeloproliferative disorders, such as agnogenie myeloid metaplasia and polycythemia Vera, splenomegaly occurs because of extramedullary hematopoiesis. In chronic myelocytic leukemia, splenomegaly occurs mainly because of the massively expanded myeloid population [30]. Splenomegaly sometimes results when the spleen is infiltrated by granulomatous tissue, by amyloidosis or when the reticuloendothelial cells contain an indigestible lipid, such as glucocerebroside in Gaucher’s disease. Also, neoplastic disorders such as lymphoma, chronic lymphocytic leukemia and, very rarely, metastatic cancer can cause splenomegaly. The spleen apparently lacks afferent lymphatics, so lymphatic spread of cancer to the spleen is rare [3l]. Even carcinomas spread to the spleen via the splenic artery rarely grow large, suggesting that the rich lymphoid tissue of the human spleen may suppress growth of carcinoma, as does the mouse spleen [32,33]. Lastly, splenomegaly may arise from cysts, hemangiomas or other malformations [34]. GIANT SPLENOMEGALY In the United.States, relatively few diseases now cause giant splenomegaly as a presenting or early feature. The largest spleens, up to 5,000 g, are usually found in the myeloproliferative disorders, agnogenic myeloid metaplasia and chronic myelocytic leukemia. Hairy cell leukemia (leukemic reticuloendotheliosis) is a newly recognized cause of giant splenomegaly and hypersplenism [35]. Isolated splenic lymphoma causes giant splenomegaly, and prior reports of this disorder probably include some patients with hairy cell leukemia [36]. Hypersplenism is occasionally the presenting feature of Gaucher’s disease. In the tropics, giant splenomegaly (tropical splenomegaly] may be seen as a result of a hyperimmune response to malaria, in which serum immunoglobulin M (IgM) levels are notably elevated [37]. An interesting counterpart, idiopathic nontropical splenomegaly, rarely occurs in persons with no obvious cause of splenomegaly at the time of diagnosis, but a

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FUNCTION-EICHNER

Claesificatlon and Etiology of Splenomegaly

Mechanism Work hypertrophy: immune response Work hypertrophy: red cell destruction Congestive Myeloproliferative Infiltrative Neoplastic

CommonExamples Subacute bacterial endocarditis; infectious mononucleosis; Felty’s Spherocytosis; thalassemia major; pyruvate kinase deficiency Cirrhosis, splenic vein thrombosis Chronic myelocytic leukemia; myeloid metaplasia Sarcoidosis; amyloid, Gaucher’s disease Lymphoma: chronic lymphocytic leukemia; metastatic cancer

recent lo-year follow-up of 10 such patients showed that in four typical splenic lymphoma developed [38]. The far-advanced stages of chronic lymphocytic leukemia and polycythemia vera often cause considerable splenomegaly, as does long-standing thalassemia major. Finally, rare causes of giant splenomegaly include sarcoidosis [39], in which hypersplenism may be a presenting or major feature, and chronic congestive splenomegaly. HYPERSPLENISM At what point does splenomegaly result in hypersplenism? Hypersplenism is a relatively imprecise term. Classically it refers to (1) splenomegaly, (21any combination of anemia, leukopenia and/or thrombocytopenia, (3) compensatory bone marrow hyperplasia, and (4 improvement after splenectomy [40,41]. Within this framework, however, different diseases may cause different forms of hypersplenism. These will be considered herein. Furthermore, an enlarged spleen can cause problems for the patient without meeting the aforementioned definition of hypersplenism. Thus, perhaps hypersplenism could be redefined to mean that the spleen in question has become more harmful than beneficial. Examples of diseases in which massive splenomegaly causes symptoms without fulfilling the strict definition of hypersplenism are chronic myelocytic leukemia and agnogenic myeloid metaplasia. Other “modern-day” prototype hypersplenism-associated diseases are listed in Table III, in which it can be seen that diverse pathophysiologic mechanisms are involved. Hairy cell leukemia may cause hypersplenism because it involves a unique variant of the B lymphocyte (most cases), which apparently arises in the bone marrow but is relatively rigid and cannot pass easily through the splenic pores. Splenic histology in this disease shows massive congestion of the red pulp [42], so the characteristic pancytopenia may occur because this large mass of rigid cells cannot easily traverse the red pulp. Cirrhosis and splenic vein thrombosis cause pancy-

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TABLE III

Etiology of Hypersplenism in Several Diseases

Disease

‘f&s/ Likely Mechanism 01Hypsrspienism

Hairy ceil leukemia Cirrhosis; spienic vein thrombosis Feity’s syndrome Thaiassemia major Hemodiaiysis splenomegaiy Gaucher’s disease Agnogenic myeioid rnetapiasia

Retention of hairy ceils in red pulp increased pooling of blood ceils immune system work hypertrophy Reticuioendotheiiai system work hypertrophy immune and reticuioendotheiiai system work hypertrophy increased pooling and flow-induced dilutional anemia Extrameduiiary hematopoiesis

topenia because the normal splenic pool of blood cells is enlarged. Normally about 30 per cent of the blood platelets in the periphery are pooled in the spleen. In addition, the spleen contains approximately 20 ml of erythrocytes and an unknown but probably marginal fraction of granulocytes [43]. When the spleen is greatly enlarged, however, there is considerably more pooling of these blood cells, up to one third of the red cell mass, for example, and pancytopenia may result. When the mechanism of the hypersplenism is simple pooling, as in congestive splenomegaly, the leukopenia is often characterized by a “balanced” diminution, so the ratio of polymorphonuclear leukocytes to lymphocytes and monocytes stays normal. Also, the leukocytes may be available when needed, so the risk of infection is not so great. These features contrast sharply with the often severe granulocytopenia and frequent infections of Felty’s syndrome. Gaucher’s disease causes pancytopenia by increased pooling, by increased reticuloendothelial cell function with phagocytosis of platelets [44] and by a dilutional anemia (seen also in certain other varieties of giant splenomegaly] in which a flow-induced portal hypertension expands the portal vascular space, decreases the TABLE IV

Medical lndfcations for Splenectomy

To control or stage basic disease Hereditary spherocytosis Autoimmune thrombocytopenia or hemoiysis Hodgkin’s disease if hyperspienic symptoms are chronic and severe Hairy ceil leukemia’ Feity’s syndrome Agnogenic myeioid metapiasia Thaiassemia major Gaucher’s disease Hemodiaiysis spienomegaiy Spienic vein thrombosis Many authorities recommend early spienectomy for this disease. l

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effective intravascular volume and causes an acceleration of albumin synthesis and an expansion of the plasma volume [45-471. The new syndrome of hypersplenism in patients undergoing renal hemodialysis apparently results from “combined” work hypertrophy. The reticuloendothelial system of the spleen is hypertrophied because of accelerated red blood cell destruction, perhaps in part attributable to the defect in uremia in the red cell hexose monophosphate shunt [48], and the immune system of the spleen is hypertrophied, apparently because of repeated viral infections, including hepatitis, and/or repeated antigenic challenge from blood transfusion or dialysis [48-511. Felty’s syndrome [52], the triad of chronic, deforming rheumatoid arthritis, splenomegaly and granulocytopenia which occurs in up to 1 per cent of patients with rheumatoid arthritis, may represent a unique variant of hypersplenism in which the spleen appears to be acting as if it were a giant lymph node. There are at least four current theories for the granulocytopenia of Felty’s syndrome: (1) decreased marrow granulopoiesis; (2) increased margination of granulocytes from the peripheral blood; (3) increased splenic sequestration of granulocytes; and (4) antigranulocyte antibodies. There are kinetic data that support the concept of increased marginal pooling of granulocytes [53] and a recent report of suppressor T cells which inhibit marrow granulopoiesis [54]. Granulocytes in Felty’s syndrome may be coated with immunoglobulin which is either an antigranulocyte antibody or part of an immune complex adsorbed to granulocytes. Titers of this immunoglobulin decrease after splenectomy [55]. MEDICAL INDICATIONS FOR SPLENECTOMY The medical indications for splenectomy are given in Table IV. Splenectomy controls, but does not cure, hereditary spherocytosis. The patient lives a normal life despite spherocytes in the blood. Similarly, the spleen is the dominant organ of cell destruction and a source of antibody production in autoimmune thrombocytopenia and in autoimmune hemolytic anemia of the warm antibody type. In these disorders, splenectomy offers good control of the disease in up to 70 per cent of the patients, although low grade destruction of the blood cells continues in other reticuloendothelial organs such as the liver. In Hodgkin’s disease, the spleen is removed as part of the staging laparotomy. In children, this procedure brings about a risk of lethal septicemia. A recent study showed that in almost 10 per cent of 200 children splenectomized for Hodgkin’s disease fulminant bacteremia developed within three years [56]. Table IV also lists several diseases in which the question of a therapeutic splenectomy often arises. In a recent review of hairy cell leukemia, serious infections developed in 40 per cent of the patients. Bacterial infections were linked with granulocytopenia, and op.

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portunistic fungal and tuberculosis infections with corticosteroid therapy. It was concluded that therapeutic splenectomy is still the treatment of choice for hairy cell leukemia, especially since chemotherapy has yet to prolong survival in this disease [57]. Splenectomy for Felty’s syndrome has long been debatable [52,58]. A recent study of 27 patients showed good long-term results from splenectomy; only three patients had persistent granulocytopenia and only one had major recurrent infections [!%I.Although it is not unanimous, common opinion holds that splenectomy is the treatment of choice for patients with Felty’s syndrome and a long history of leg ulcers or substantial and recurrent infections. Splenectomy at least remains the standard against which to test newer proposed therapies such as testosterone, lithium or gold. Granulocytes in Felty’s syndrome may, however, have functional defects which may not necessarily be influenced by splenectomy J601. Splenectomy has been performed in advanced agnogenic myeloid metaplasia because of repeated splenic infarcts and rapid red cell destruction. In a recent study, 19 patients with agnogenic myeloid metaplasia underwent elective splenectomy at diagnosis [61]. The investigators concluded that the hematologic status and quality of life improved after splenectomy in 17 patients and that the results warranted a further trial of elective splenectomy in agnogenic myeloid metaplasia. How’ever, mean follow-up time was only 19 months. In long-standing thalassemia major, therapeutic splenectomy is often required [62]. It seems likely, however, that high transfusion regimens coupled with effective iron depletion technics may largely prevent severe hypersplenism and reduce the need for splenectomy in thalassemia major. Recent studies of splenectomy for palliation of advanced chronic myelocytic and lymphocytic leukemia have shown only marginal gains with substantial postoperative complications, and the role of splenectomy in these diseases remains controversial [63,64]. At present, there is no evidence that early splenectomy in these chronic leukemias prolongs over-all survival. As mentioned earlier, the data from several groups suggests that hypersplenism develops in from 5 to 10 per cent of the uremic patients undergoing long-term hemodialysis. Therapeutic splenectomy is increasingly being performed in such patients [5l]. Finally, splenic vein thrombosis, thought commonly to be caused by pancreatic disease, is a cause of hypersplenism and variceal bleeding which can be cured by splenectomy [65]. HYPOSPLENISM

The concept of hyposplenism is not as time-honored as that of hypersplenism, but severe hyposplenism is a potentially lethal condition. Hyposplenism was firmly established by Dameshek [66] in 1955 when he reported

a case of nontropical sprue and hyposplenism first suspected because of Howell-Jolly bodies and target cells in the peripheral blood smear. Additional peripheral smear clues to hyposplenism are acanthocytes and siderocytes [25]. After splenectomy there are chronic changes in the complete blood count which also serve as hematologic clues to the asplenic state [67]. Granulocytosis occurs immediately after splenectomy and in several weeks is replaced by long-lived lymphocytosis and monocytosis, which fits with the observation that the normal spleen selectively removes lymphocytes and monocytes from the blood [7]. Thrombocytosis occurs immediately after splenectomy, but within two weeks the platelet couni usually returns to high-normal levels. However, if the patient has a continuing hemolytic [68] or sideroblastic [69] anemia with the concomitant active bone marrow, or if the patient has an underlying myeloproliferative disease [7O], the postsplenectomy thrombocytosis may be severe and sustained with platelet counts exceeding 1 million/mm3 and with the risk of hemorrhage and of fatal thromboembolism. In severe cases, chemotherapy may be required to lower the platelet count. These hematologic clues should lead the physician to suspect hyposplenism. Confirmatory tests include splenic scan [7l], the quantitation by interference phase microscopy of red blood cell surface pits and craters, which are increased after splenectomy [24], and the determination of splenic uptake of heat-damaged, radiolabeled red blood cells [72]. Clinically, the spleen scan is all that is required to confirm hyposplenism. For research purposes, the heat-damaged red cell uptake is more sensitive to subtle abnormalities of splenic function, but this test is markedly infiuenced by the degree of damage to the red cell [72]. If damage is minimal, the spleen will not remove the cells avidly, whereas if damage is severe, the liver will also remove these cells. Another clinical prototype of hyposplenism is the child with sickle cell anemia who is vulnerable to overwhelming, often fatal, pneumococcemia. Ironically, the child is at greatest risk when the spleen is enlarged, not when it is later atrophic from “autosplenectomy.” Children with sickle cell anemia and enlarged spleens have functional asplenia, and transfusion can temporarily reverse this phenomenon, presumably by restoring the splenic circulation and phagocytic activity to normal by reducing the load of fixed sickled cells [73,74]. As the child grows older, the spleen shrinks because of repeated infarcts. However, the child gains immunity to the different serotypes of pneumococcus and more reliance can be placed on the liver for clearance of blood-borne pneumococci. However, we have reported fatal pneumococcemia in a 16 year old boy with sickle cell anemia who had been active and in good health for five years before the sudden, fatal illness [75]. Also, transient functional hyposplenism has recently

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TABLE V

Diseases Linked with Hyposplenlsm Atrophic spleen Ulcerative colitis Celiac disease Dermatitis herpetiformis Thyrotoxicosis (Graves’) Hemorrhagic thrombocythemia Thorotrast Normal-sized or large spleen Sickle cell anemia Sarcoidosis Amyloidosis Highdose corticosteroids?

been reported in a 22 year old woman with SC hemoglobin during a painful crisis [76]. There are a wide variety of conditions associated with hyposplenism (Table V). The classic association has been splenic atrophy with celiac sprue or idiopathic steatorrhea, with more than 50 cases reported [77,78]. Recent studies have shown that up to 40 per cent of the patients with either celiac sprue or dermatitis herpetiformis have evidence for hyposplenism on peripheral blood smear or by splenic uptake studies [79]. Although the mechanism of hyposplenism in these disorders remains unknown, it has been linked with the generalized lymphoreticular atrophy noted in celiac sprue [80] and with the recent autoimmune theory of pathogenesis of celiac sprue, supported by its link with the HL-A8 histocompatibility antigen and frequency of autoantibodies [81]. A review of hyposplenism with sprue suggests that the risk of pneumococcemia is not great; perhaps enough splenic activity remains to defend against bacteremia. In a recent study, hospital patients were screened for Howell-Jolly bodies and target cells on peripheral blood smear. Six of the 12 such patients had celiac sprue, two had discoid lupus, and two had Graves’ disease [81]. There are now at least five reported cases of hyposplenism of unknown origin in Graves’ disease [82]. Clearcut hyposplenism has been documented in three of eight patients with hemorrhagic thrombocythemia, a relatively well-defined myeloproliferative disease in which the major abnormality is excessive production of megakaryocytes and platelets. In this disease, splenic atrophy can occur because of repeated infarcts from large aggregates of platelets [83]. Also, there are several reports of splenic atrophy and one report of fatal pneumococcemia in patients who had received thorium dioxide (ThorotrastR) as a radiocontrast agent [84]. The alpha irradiation from this long-lived isotope, which remains in the reticuloendothelial cells, causes fibrosis and atrophy of the spleen and can also cause liver cancer. Next to sickle cell anemia, perhaps the most threatening link between disease and hyposplenism is ulcerative colitis [85]. Although patients with ulcerative

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colitis do not have hyposplenism at the time of diagnosis, it develops in about 40 per cent during the disease, and the hyposplenism waxes and wanes with activity of the colitis. Hyposplenism becomes severe when pancolitis develops; this helps to explain the link between thrombocytosis and active ulcerative colitis [86]. When patients with pancolitis and hyposplenism require colectomy, there is a high risk of postoperative septicemia, which on occasion is pneumococcal and fatal [85]. Hyposplenism is rarely seen with regional enteritis. The mechanism of severe hyposplenism in aggressive ulcerative colitis remains a mystery. Hyposplenism, or functional asplenia, occurs even with normal-sized or large spleens (Table V). A recent report documents fatal pneumococcemia in an apparently healthy woman in whom autopsy disclosed that a 300 g spleen had been totally replaced by granulomatous tissue from sarcoidosis [87]. Also, in two of 36 patients with light chain myeloma, peripheral smear and splenic scan disclosed evidence of hyposplenism from amyloidosis [88], which may account for part of the risk of repeated pneumococcal infections and pneumococcemia in multiple myeloma. Finally, the documented effect of high-dose corticosteroid therapy in blocking splenic monocyte destruction of antibody-coated platelets and red cells in autoimmune thrombocytopenic and hemolytic states [89] suggests that high-dose cortidosteroid therapy, in general, may impair splenic phagocytic activity and increase the risk of overwhelming bacteremia. FULMINANT BACTEREMIA IN HYPOSPLENISM The hyposplenic state is potentially lethal because of the risk of fulminant bacteremia [QO].This risk is greatest in young children who are splenectomized, especially for the first two years after surgery (80 per cent of cases), and when the disorder for which the splenectomy was required is a disease of the reticuloendothelial system such as thalassemia major, histiocytosis X or the Wiscott-Aldrich syndrome (20 per cent risk of septicemia) [91,92]. The high risk in children splenectomized during the staging laparotomy for Hodgkin’s disease has been mentioned. Fulminant septicemia seems rare after splenectomy for hereditary spherocytosis; Schilling followed 61 patients for almost 800 postsplenectomy years (collectively] without encountering a single case [93]. Nonetheless, there is a low but significant risk even in normal subjects who have incidental splenectomy [62]. In recent years up to 50 cases of serious and often fatal postsplenectomy septicemia have been reported in adults, many of whom underwent splenectomies for trauma. Although the actual risk of fulminant bacteremia in these normal subjects remains unknown, some investigators have estimated it to be as high as 0.5 to 1 per cent per year after splenectomy [94]. The longest reported interval between incidental splenectomy and overwhelming bacteremia has been 25 years [95]. In the

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typical syndrome, a previously healthy, normal adult has a high fever, usually after a brief mild upper respiratory tract infection, and within hours experiences shock and disseminated intravascular coagulation which often prove fatal [90,92,96]. These patients have no obvious site of pneumococcal infection; the bacteremia is of cryptic origin. However, it is speculated that the nasopharynx is the site of infection and that a synergistic viral infection is needed to convert an asymptomatic carrier state into a fulminant pneumococcemia [96]. In this fulminant syndrome, blood levels of pneumococci reach extraordinary proportions, seen only in patients with hyposplenism, and the capsular polysaccharides of these organisms trigger bacterial shock and disseminated intravascular coagulation [97,98].The peripheral blood smear reveals telltale signs of vacuolated polymorphonuclear leukocytes, thrombocytopenia and even pneumococci, both free and within polymorphonuclear leukocytes [75,99]. Although the pneumococcus has accounted for most cases, there have been reports, especially in children, of fatal septicemia caused by meningococcus or by H. influenzae. The threat of fatal pneumococcemia after splenectomy for trauma may be reduced because of the “born-again” spleen, or splenosis [loo], which has recently been demonstrated in about half of the subjects previously splenectomized for trauma and which can be detected as early as one and a half years after surgery [loll. Presumably these “minispleens” function well enough to protect against fatal pneumococcemia. This has led to the suggestion that certain patients receive splenic autotransplants at the time of splenectomy [5,102]. Although this novel suggestion merits study, there are reports in children [IO31and adults [90,96,104] of lethal postsplenectomy septicemia despite the presence of at least 25 g of residual splenic tissue at autopsy. Furthermore, animal work has shown that splenic autotransplants, although they restore the normal immunoglobulin response to intravenously administered particulate antigen [105], do not protect from death from intravenous pneumococci [106]. The doses in these studies, however, were high. MANAGEMENT OF SEPTICEMIA THREAT IN HYPOSPLENISM What can we do about the threat of fatal bacteremia in hyposplenism? First, physicians should be aware of the diverse diseases associated with hyposplenism and of the hematologic clues to hyposplenism. Probably fewer splenectomies should be performed after splenic trauma. In fact, surgical management of splenic trauma is moving toward nonsurgical approach in some cases and toward surgical repair in other cases, analogous to surgical management of liver trauma [107]. Bacterial vaccines should be used in patients with hyposplenism. A recent study demonstrated significant protection from pneumococcemia in children with sickle cell anemia

who were followed for two years after receiving an octavalent pneumococcal vaccine [108]. The commercial pneumococcal vaccine (Pneumovax] should be given to children with sickle cell anemia, to children splenectomized for Hodgkin’s disease, to adults after incidental splenectomy (asplenic hosts respond normally to subcutaneous immunization] and probably to patients with the diseases associated with hyposplenism. All these patients might also be given the vaccines for types A and C meningococcus, and, when they become available, the vaccines for type B meningococcus and for H. influenzae. Since the pneumococcal vaccine has not yet been proved effective in children under two years of age, perhaps prophylactic penicillin should be given for two years to infants born with sickle cell anemia. One could also recommend prophylactic penicillin for patients with ulcerative colitis and hyposplenism who are to undergo colectomy. Asplenic subjects or those with diseases linked with hyposplenism in whom fevers develop without obvious sites of infection should be treated as medical emergencies. They should immediately see a physician who should obtain cultures and treat them expectantly for pneumococcemia with intravenous penicillin. Perhaps an aggressive approach to such patients will save lives by eliminating pneumococci from the blood stream before the lethal chain of events has begun. Physicians need a reliable clinical index of early pneumococcemia. We studied prospectively the value of scoring vacuolization of polymorphonuclear leukocytes, previously reported to be a morphologic index of bacteremia [log], as a predictor of septicemia in febrile children. Unfortunately, neutrophil vacuolization did not predict septicemia and was not even specific for bacterial infection [IIO]. Heavily vacuolated cells are a late and nonspecific sign of bacteremia. Further investigation is required in order to determine dependable guidelines for early bacteremia. Finally, the question of splenic autotransplant for selected patients deserves further study. ADDENDUM In recent articles, fatal pneumococcemia diagnosed by peripheral blood smear in a patient with multiple myeloma and an apparently normal spleen was reported [Ill], and the still limited indications for splenectomy in chronic myelocytic leukemia outlined [112], In two recent reviews of hairy cell leukemia [113,114], the investigators seemed to agree that early splenectomy, as opposed to splenectomy for symptomatic pancytopenia, is not necessarily beneficial. In recent abstracts it was reported that splenosis after splenectomy for trauma occurs as frequently in adults as it does in children [II51 and, in an animal model, that postsplenectomy septicemia is facilitated by a concurrent viral infection [116].

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