The Asplenic Patient: Post-Insult Immunocompetence,Infection,and Vaccination

Abstract

Background:

Splenic injury can occur through multiple mechanisms and may result in various degrees of residual immunocompetence. Functionally or anatomically asplenic patients are at higher risk for infection, particularly with encapsulated bacteria. Vaccination is recommended to prevent infection with these organisms; however, the recommendations are routinely updated, and vaccine selection and timing are complex.

Methods:

Review of the pertinent English-language literature, including the recommendations of the U.S. Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices.

Results:

Overwhelming post-splenectomy infection is associated with high morbidity and mortality rates. Patients requiring splenectomy for trauma-related injury appear to be at lower risk for infection than those undergoing splenectomy for a hematologic or oncologic indication. Initial vaccination is dependent on immunization history but generally should consist of the 13-valent pneumococcal conjugate, quadrivalent meningococcal conjugate, meningococcal serogroup B, and Haemophilus influenzae serotype b (Hib) vaccines. Antimicrobial prophylaxis for certain asplenic patients, such as children under the age of five y, may be indicated.

Conclusion:

Immunization remains a key measure to prevent overwhelming post-splenectomy infection. Consideration of new recommendations and indications, possible interactions, and timing remains important to including optimal response to the vaccines.

The spleen was once viewed as a superfluous organ, similar to the appendix, and it was removed with impunity if injured. It was not until the 19^th Century that the spleen was first associated with immune function [1]. The earliest association linking splenectomy to life-threatening infection was reported by Morris and Bullock in 1919 when they demonstrated a four-fold increase in lethal infection with Bacterium enteritidis (now known as Salmonella enterica serotype Enteritidis) in splenectomized rats [2]. Subsequently, King and Shumacker reported five cases of severe infection in infants following splenectomy for spherocytosis [3]. Additional reports confirmed these observations, and the term “overwhelming post-splenectomy infection” (OPSI) was popularized by Diamond in 1969 [4].

The asplenic population is heterogenous and includes patients with surgical, functional, and congenital asplenia. Surgical asplenia may occur in otherwise healthy patients after traumatic injury or in patients with an underlying hematologic or immunologic indication for splenectomy such as hereditary spherocytosis, immune thrombocytopenic purpura, or lymphoma [5]. In patients with sickle-cell anemia, functional asplenia develops by approximately one y of age, and anatomic asplenia secondary to autoinfarction develops after six to eight y of age [6]. Chronic graft-versus-host disease after stem cell transplantation, severe celiac disease, and untreated human immunodeficiency virus infection are the disease states now most likely to be associated with hyposplenism; as many as 50% of patients with these conditions have impaired splenic function. Congenital asplenia is a rare condition that may be isolated but is more likely to be associated with other anomalies, particularly congenital heart disease (Ivemark syndrome) [7,8]. Approximately 25,000 splenectomies are performed annually in the United States, and the total number of asplenic persons in the United States is estimated at 1 million currently, including approximately 100,000 persons with sickle-cell disease [9, 10].

Splenic Function

Because of its unique architecture and abundant blood flow, the spleen plays a prominent role in the defense against blood-borne organisms. Ninety percent of arterial blood flow to the spleen is directed through the red pulp and circulates in the meshwork of splenic cords before passing through the endothelial pores of the splenic sinuses [11]. Because of the organization of the microcirculation, blood-borne bacteria remain in contact with splenic phagocytes, allowing clearance even of poorly opsonized bacteria.

Invasive, encapsulated bacterial pathogens possess a surface polysaccharide capsule that impedes opsonization by immunoglobulin or complement in the circulation. The spleen plays an important role in the production of immune mediators that aid in the clearance of bacteria and viruses. These mediators, known as opsonins, coat circulating bacteria and viruses and convert them into immune complexes. Although the liver clears some of these circulating immune complexes, the spleen is predominant in their removal [11].

The spleen also produces tuftsin, a tetrapeptide that stimulates phagocytosis. Tuftsin binds to specific receptors on granulocytes, monocytes, and natural killer cells [12]. Once activated, tuftsin modulates the biologic activities of phagocytic cells [13]. Moreover, the spleen produces properdin, an opsonin that plays a crucial role in the alternative pathway of complement activation. This pathway is activated in the absence of antibody and generates both soluble and membrane-bound forms of C3 convertase, an enzyme that catalyzes the proteolysis of C3. The alternative pathway form of C3 convertase decays rapidly unless it is stabilized by binding with properdin. Binding of properdin with C3 convertase allows conversion of C3 to C3b.

An exclusive function of the spleen is clearance of intraerythrocytic inclusions while maintaining the integrity of the red blood cell. The inclusions removed by the spleen include particulate matter, Heinz bodies (denatured hemoglobin), Howell-Jolly bodies (nuclear remnants), and Papenheimer bodies (iron granules). Red blood cells must deform to pass through the slit-like fenestrations of the sinus endothelium. Rigid inclusions, unable to transverse the narrow passage, are entrapped, excluded from the cell, and phagocytized by the resident macrophages [14]. Asplenic and hyposplenic patients lose their ability to clear damaged red blood cells and inclusions from the circulation. These patients display a variety of abnormal erythrocytes in the peripheral blood, whose presence may be used as a marker of splenic dysfunction [15].

Consequences of Asplenia

Several lines of evidence suggest that post-splenectomy patients have compromised humoral immunity, deficient in both complement and immunoglobulin. A particular subset of circulating memory B cells (IgM memory B cells), which respond to bacterial polysaccharides, are absent in congenitally asplenic patients and are severely depleted immediately after splenectomy [16]. Memory B cells are highly specific, long-lived cells generated in germinal centers after somatic mutation, selection, and class switch in response to a specific etiologic pathogen or vaccine. They persist and produce antibodies rapidly after a second challenge with the same antigen. In humans, 30%–60% of B cells are considered memory B cells, one-half of which are IgM memory B cells. The IgM memory cells are dependent on a functional spleen for their generation and survival and are responsible for the T-cell-independent response to bacterial polysaccharides [17].

Post-splenectomy patients also lack properdin, which may contribute to the risk of OPSI [15]. The amount of tuftsin is significantly reduced after splenectomy as well. Szendroi et al. demonstrated a return to normal tuftsin concentrations in children after splenectomy for trauma following autotransplantation of minced splenic tissue into the omentum [18].

Currently, non-operative treatment is attempted in 60%–90% of patients with blunt splenic injury [19,20]. Liberal use of angioembolization of the proximal or distal splenic artery or both has been reported to increase the utilization of non-operative management and to decrease failure rates [21,22]. However, whether the injury itself or splenic artery angioembolization impairs splenic function remains controversial. To date, no specific marker of splenic immune function has been identified, and such function is assessed by indirect tests of the spleen's viability, hemofiltration, and immunologic functions [23,24]. Patients sustaining severe (American Association for the Surgery of Trauma grades IV and V) blunt splenic trauma who have been managed non-operatively are theoretically at risk for OPSI because of injury to a significant proportion of the parenchyma, architecture, and blood supply. In a study of 40 patients, Falimirski et al. utilized the red blood cell pit test (RBCPT), a common test to evaluate splenic-based immunocompetence in patients with sickle cell anemia and other hemoglobinopathies, to study immune function in patients with high-grade splenic injury. All patients with grade IV/V injuries managed non-operatively and “pit tested” showed the same pit counts as the group that had not sustained a traumatic injury. When the same injury group was compared with a splenectomy control group, a significant increase was noted in pit counts of post-splenectomy patients, suggesting immunocompetence after splenic injury [25].

Bessoud et al. examined 24 patients after proximal angioembolization of the splenic artery, reporting normal-size and well-perfused spleens with Howell-Jolly bodies present in only two patients and a sufficient immunoglobulin response to Haemophilus influenzae and Streptococcus pneumoniae (pneumococcus) [26]. Tominaga et al. detected no significant immunologic differences between patients who had undergone angioembolization or splenectomy vs. healthy controls except for higher cytotoxic T cell numbers in those who had undergone splenectomy [27]. Malhotra et al. reported that T-cell subgroups found after angioembolization were similar to those in healthy controls [28]. Studies of immune function after splenic injury and angioembolization are not sufficient to support any firm conclusions about preservation of splenic immunocompetence but appear to support the view that immune function may be preserved [29,30]. However, a recent retrospective study of patients with blunt splenic injury found that angioembolization was associated with a risk of infection-related readmission similar to that after splenectomy [20]. It appears that vaccination may be unnecessary in adults after non-operative management without angioembolization, but determinations regarding immunization of patients undergoing angioembolization should be based on a shared decision by the individual patient and the healthcare provider.

Infectious Complications in Asplenia

Overwhelming post-splenectomy infection is a fulminant, potentially life-threatening condition that may occur weeks to years after removal of the spleen. The precise incidence of OPSI remains controversial. All data on the sepsis risk among patients who have undergone splenectomy predated the 2000 introduction of universal vaccination with heptavalent pneumococcal conjugate vaccine (PCV7) in children in the United States. This vaccine has reduced markedly the incidence of invasive pneumococcal disease among children younger than five y and also has lowered the likelihood of invasive disease in all age groups as a result of herd immunity. The 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in 2010, resulting in additional reductions in invasive pneumococcal disease in young children and adults as a result of coverage of more serotypes. The specific benefit of pneumococcal vaccination in reducing invasive pneumococcal disease in post-splenectomy patients has not been well characterized; however, a multicenter study found that of 17 patients with pneumococcal OPSI, only two had received pneumococcal vaccine within the past five y compared with five patients having vaccination more than five y prior and 10 with no history of vaccination [31]. One of the most reliable reports relating to the incidence of OPSI is that of Schwartz et al., who applied actuarial methods to a population free of selection bias that had consistent long-term followup. The risk of OPSI was estimated to be about one case per 500 person-years of observation. However, the cumulative risk of infection severe enough to necessitate hospitalization was 33% by the end of 10 y [32].

Splenectomy performed for a hematologic disorder such as hereditary spherocytosis, thalassemia, or lymphoma carries a higher risk of sepsis than trauma-related splenectomy. One study calculated the risk of sepsis as 0.73 per 1,000 person-years after splenectomy for hereditary spherocytosis [33]. Thalassemia major appears to carry the highest risk of post-splenectomy infection among patients with inherited hematologic disorders (8.2%) [34]. Patients with Hodgkin disease, particularly those who received chemotherapy, may be at the greatest risk, with sepsis occurring in 25%–33% of these patients [35,36].

A potential contributor to the lower rate of infection after trauma-related splenectomy is the frequent existence of splenic implants or accessory spleens [37]. Small implants of splenic tissue (splenosis) are found in the peritoneum of 50% of patients who undergo splenectomy for trauma. About 10% of such patients also have accessory spleens [38]. Animal studies suggest that a splenic remnant of approximately 25% is required to preserve immune function [39]. Unfortunately, the degree of protection offered by splenosis or accessory spleens is both variable and unpredictable. Patients with splenic remnants also often receive vaccination against encapsulated bacteria, making it difficult to determine whether it is the remaining splenic tissue or the vaccines that are protective [40,41]. A number of cases of OPSI have been reported in the presence of residual splenic tissue or splenic implants [42].

Time since splenectomy also appears to affect the risk of severe infection. Several studies have shown that 50%–70% of hospital admissions for serious infections occur within the first two y, and as many as 80% of OPSI cases occur within this timeframe after splenectomy in young children [38,43]. However, some degree of risk persists indefinitely. Thirty-three percent of post-splenectomy pneumococcal infections and 42% of OPSI episodes occur more than five y after splenectomy, and individual cases of OPSI more than 40 y after splenectomy have been reported [44].

The clinical presentation of OPSI is non-specific. Most commonly, patients present with a short prodrome of fever, chills, sore throat, muscle aches, vomiting, or diarrhea. Often, there is no localizing sign of infection, and a cryptic source originating in the nasopharynx is postulated. In children younger than five y, focal infections, particularly meningitis, are more common [44]. Gastrointestinal symptoms should never distract the physician from entertaining the diagnosis of OPSI. Many patients have had true rigors for a day or two before receiving definitive medical management [45]. Prodromal symptoms may be followed by rapid evolution to bacteremia and septic shock accompanied by anuria and disseminated intravascular coagulation.

Despite appropriate antibiotics and intensive therapeutic intervention, the overall mortality rate in older published studies of documented cases of OPSI ranged from 50%–70% [45,46]. More recent information suggests that when informed patients seek medical attention promptly, their mortality rate may be reduced to approximately 10%. Of patients who die, more than 80% do so within the first 48 h after hospital admission, illustrating the importance of early diagnosis and therapy.

Most serious infections after splenectomy are caused by encapsulated bacteria. Infections with S. pneumoniae account for approximately 50%–80% of reported cases, with a mortality rate as high as 60%. Neisseria meningitidis (meningococcus), Streptococcus pyogenes (Group A), Escherichia coli, and Staphylococcus aureus account for an additional 25% of infections. Haemophilus influenzae serotype b infections are now rare in the United States because of the universal use of Hib conjugate vaccine. Other rarely implicated organisms are Capnocytophaga canimorsus, which can cause fulminant sepsis after dog bites; Streptococcus agalactiae (Group B); Enterococcus spp.; Bacteroides spp.; and Pseudomonas aeruginosa. The post-splenectomy host also is more susceptible to infections with intraerythrocytic organisms. For example, babesiosis, an infection transmitted by bites from the tick Ixodes scapularis, has been responsible for a fulminant hemolytic febrile state in asplenic individuals, and hyperparasitemia and delayed clearance of Plasmodium falciparum malaria has been reported in asplenic hosts [47 –49].

Like adults, children may become functionally or anatomically asplenic after surgery (e.g., splenectomy) or trauma. Etiologies for asplenia that are more frequent in the pediatric population include insults to the vascular supply of the spleen in early childhood (e.g., sickle-cell disease resulting in functional asplenia) or congenital absence of the spleen or polysplenia [50]. Such children are at a significantly greater risk of bacterial infections, primarily from the same encapsulated organisms that affect adults [50,51]. The risk of post-splenectomy sepsis is highest in young children, especially those younger than two y, with a markedly decreased incidence after the age of three to five y [52]. The risk of death also is higher in children [34]. A collective critical review of the literature on OPSI from 1952 to 1987 showed that the incidence in children under 16 y of age was 4.4% with a mortality rate of 2.2% with the respective corresponding rates for adults being 0.9% and 0.8% [35]. The incidence of sepsis after splenectomy caused by trauma was 15.7% in infants and 10.4% in children younger than five y [35]. Regardless of age, the risk of serious infection is highest in the first year after splenectomy [50]. However, a higher risk of bacterial sepsis compared with individuals with normal splenic function persists for life, even beyond childhood [34, 50]. Some studies have estimated the risk of septicemia and death in asplenic children to be 350-fold higher than that in children with a functional spleen [53]. The risk of infection also differs by the etiology of asplenia, with thalassemia and sickle-cell anemia patients at higher risk than those with asplenia resulting from trauma [34].

Antimicrobial Prophylaxis

In addition to immunizations, providers should consider antimicrobial prophylaxis with penicillin in children younger than five y of age and for at least one y after splenectomy at any age. Oral doses of 125 mg bid for children under five y of age and 250 mg bid for children beyond this age are recommended [53,54]. Amoxicillin (20 mg/kg/day) may be substituted, particularly for children unable to swallow tablets, given the poor taste of liquid penicillin [53]. For penicillin-allergic patients, erythromycin (250 mg bid) may be utilized [53]. Antimicrobial prophylaxis may be discontinued at the age of five y in a child with sickle-cell disease who has not had severe pneumococcal infection, is up to date on immunizations, and has access to medical care [53,54]. The optimal duration of antimicrobial prophylaxis in other forms of asplenia in children is not well studied.

Vaccination

General vaccine guidance—adults

The selection and timing of vaccines for patients with asplenia is determined by a patient's immunization history. If the history for any recommended vaccine is unknown, it should be assumed that the patient has not received that specific immunization. Patients undergoing an elective splenectomy should receive the initial pneumococcal, meningococcal, and Hib vaccines at least 14 d prior to surgery, as it may take as long as two wks for the patient to develop immunity after vaccination [55,56]. If an emergency splenectomy is performed, patients should complete initial vaccinations prior to discharge to ensure the vaccines are received. The optimal antibody response to polysaccharide vaccines may occur when they are given at least 14 d after surgery [57]; however, it is not clear if this recommendation also applies to conjugate vaccines.

Pneumococcal vaccination

In the United States, both the 13-valent conjugate vaccine (PCV13; Prevnar 13) and the 23-valent polysaccharide vaccine (PPSV23; Pneumovax 23) are recommended in asplenic patients [58]. Previously unvaccinated asplenic patients should receive PCV13 first followed by PPSV23 at least eight wks later (Table 1). The shorter interval of eight wks between vaccines is recommended by the U.S. Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices to minimize the time until immunity to the 11 additional serotypes included in PPSV23 [59]. A one-time booster dose of PPSV23 should be given at least five y after the first. If a patient has already received a dose of PPSV23, administration of PCV13 should occur at least one y after PPSV23, as administration at a shorter interval may result in a decreased immune response to subsequent doses of both PCV13 and PPSV23 [60 –63]. If a patient has received PCV13 already, additional doses are not required, and PPSV23 may be given in its place. Patients may receive one additional dose of PPSV23 after age 65 (lifetime maximum of three doses) if they were younger than 65 at the time of the first two doses.

Table 1.

Timing of Adult Splenectomy Vaccinations Based on Initial Vaccinations

Preferred regimen
	Timing of vaccine boosters from initial vaccination
Initial vaccinations	≥ 4 wks	≥ 8 wks	≥ 12 wks	≥ 6 mos	≥1 y
• PCV13 • MenACWY-CRM • MenB-4C • Hib	—	MenACWY-CRM MenB-4C PPSV23	—	—	—

Alternative regimens (if unable to give preferred regimen above)
	Timing of vaccine boosters from initial vaccination
Initial vaccinations	≥ 4 wks	≥ 8 wks	≥ 12 wks	≥ 6 mos	≥1 y
• PCV13 • MenB-4C • Hib	MenACWY-D MenB-4C	—	MenACWY-D PPSV23	—	—
• PCV13 • MenACWY-CRM • MenB-FHbp • Hib	—	PPSV23 MenACWY-CRM MenB-FHbp	—	MenB-FHbp	—
• PPSV23 • MCV4 • MenB-4C • Hib	—	MCV4 MenB-4C	—	—	PCV13
• PPSV23 • MCV4 • MenB-FHbp • Hib	—	MCV4 MenB-FHbp	—	—	PCV13 MenB-FHbp

Note: this table provides timing to minimize number of visits for vaccination and assumes no previous vaccination with any of the vaccines.

PCV13 = 13-valent pneumococcal conjugate vaccine (Prevnar 13); PPSV23 = 23-valent pneumococcal polysaccharide vaccine (Pneumovax 23); MenACWY-CRM = quadrivalent meningococcal conjugate vaccine (Menveo); MenACWY-D = quadrivalent meningococcal conjugate vaccine (Menactra); MCV4 = quadrivalent meningococcal conjugate vaccine; MenB-4C = serogroup B meningococcal vaccine (Bexsero); MenB-FHbp = serogroup B meningococcal vaccine (Trumenba); Hib = Haemophilus influenzae serotype b vaccine.

Meningococcal vaccination

There are five meningococcal vaccines available in the U.S. The two quadrivalent conjugate vaccines (MCV4) can be used interchangeably. However, one of these vaccines (MenACWY-CRM; Menveo) is approved for use in patients two mos of age or older, whereas the other is approved for use in those age nine mos or older (MenACWY-D; Menactra) [64,65]. Additionally, MenACWY-D should be separated from PCV13 by at least four wks, as co-administration results in a lesser immune response to certain serotypes found in PCV13 [65]. In the previously unvaccinated patient, a second dose of MCV4 should be given at least eight wks after the first. Patients who have previously received MCV4 require either a single dose if it has been more than 5 y since vaccination or no peri-operative doses if the vaccine was given within the past 5 y. All patients should receive a booster dose every five y after the most recent administration.

Recently, two meningococcal serogroup B (MenB) vaccines have been developed and are recommended for asplenic patients 10 y old or greater [66]. MenB-4C (Bexsero) is U.S. Food and Drug Administration (FDA)-approved as a two-dose series administered at least one mo apart, whereas MenB-FHbp (Trumenba) can be administered as either a three-dose series given at 0, one to two, and six mos or a two-dose series given at 0 and six mos; however, ACIP recommends that if MenB-FHbp is selected for asplenic patients, it should be given as the three-dose series. Additionally, these vaccines are not interchangeable, and patients should complete the series with the same vaccine they receive initially [67]. There are no recommendations for booster doses of MenB after completion of the initial series. Co-administration of MenB-4C with PCV7, MenACWY-CRM, or a combination vaccine containing Hib had no effect on the immunogenicity of any serotypes studied [68 –70]. MenB-FHbp has been effective with MenACWY-D, but co-administration with a pneumococcal or Hib vaccine has not been studied [71]. Meningococcal vaccines may be given concurrently (e.g., MCV4 and MenB) but should be administered at separate sites.

A tetravalent polysaccharide vaccine (MPSV4; Menomune) also exists, but it is not recommended for use in patients requiring multiple doses (i.e., asplenic patients) regardless of the patient's age [72]. If a patient previously received a dose of MPSV4, a two-dose series of MCV4 should be given due to concern for an inadequate booster response to a single dose of MCV4 [73].

Hib vaccination

The Hib vaccine is available as a monovalent conjugate (ActHIB, Hiberix, and PedvaxHIB) given once. If a patient previously received the Hib vaccine series, revaccination is not required. However, some experts believe that patients who have completed the series and are undergoing an elective splenectomy may benefit from one additional dose at least 14 d before surgery [53].

General vaccine guidance—children

Immunizations may help prevent overwhelming bacterial infection in asplenic children, although the type of vaccine and the timing of immunization are important factors to consider [52]. Given the increasing number of pediatric immunizations available, which may have different administration intervals or be approved for different ages, and the growing complexity of immunization schedules for children compared with adults, the appropriate vaccination of a child prior to or after splenectomy may be more challenging than in an adult.

As in adults, optimization of the immunologic response to immunization may be best if immunizations are completed two or more wks prior to elective splenectomy [53,56,57,74 –76]. For non-elective/urgent splenectomies, waiting two wks after splenectomy produces a more robust functional antibody response in adults receiving pneumococcal polysaccharide vaccines [53,57]. However, the timing of immunization after splenectomy has not been well studied in children, nor is it well studied with conjugate vaccinations. Given the lack of data on the optimal timing of immunization in children after non-elective/urgent splenectomies, immunization prior to hospital discharge after splenectomy should be considered (even if this occurs within two wks of the operation) in order to ensure compliance with immunizations. This is particularly true if there are concerns regarding the ability of the child to receive appropriate medical followup.

Pneumococcal vaccination

As PCV13 is part of the recommended pediatric immunization schedule, it is important to determine the number of doses previously received, if any. This can be determined through the parents or guardians, medical records, or statewide vaccine reporting systems. The number of doses of PCV13 required peri-operatively is based on patient age and the number of doses (Table 2). After the last dose of PCV13 is administered, all children over the age of two y should receive a dose of PPSV23 ≥ 8 wks, and then ≥5 y later [53, 75, 76]. Children under the age of two y should not receive PPSV23 [53, 75, 76]. No more than two total doses of PPSV23 should be administered prior to age 65 [53]. If PPSV23 has been received but PCV13 has not, any necessary PCV13 immunizations should start ≥8 wks after the last dose of PPSV23.

Table 2.

Pediatric Pneumococcal Vaccination Schedule after Splenectomy

	Doses of pneumococcal vaccine (PCV7 or PCV13) received prior to splenectomy
Age (y)	Not immunized	1–2	3	4
<2	Refer to CDC Guidelines	Refer to CDC Guidelines	1 of PCV13 ≥ 8 wks after last dose	Not indicated
2–5	2 of PCV13 ≥ 8 wks apart	2 of PCV13 ≥ 8 wks apart	1 of PCV13	1 of PCV13 if only PCV7 received previously
6–18 years	1 of PCV13	Not indicated	Not indicated	Not indicated

PCV13 = 13-valent pneumococcal conjugate vaccine (Prevnar 13); PCV7 = heptavalent pneumococcal conjugate vaccine (Prevnar 7).

Meningococcal vaccination

All children at least eight wks of age undergoing splenectomy should be immunized with MCV4. The number of doses and the timing of the primary series and boosters is determined by the age of the child (Table 3). Children initiating meningococcal immunization between two and six mos of age should receive a four-dose primary series of MenACWY-CRM at two, four, six, and 12 mos of age [53, 76]. Children initiating meningococcal immunization between seven and 23 mos of age should receive a two-dose series of MenACWY-CRM given at least 12 wks apart and with the second dose given after the child reaches one y of age [76]. The MenACWY-D vaccine should be avoided in children under two y of age because of interference with the serologic response to the pneumococcal conjugate vaccine [53,76]. Children older than two y may receive a two-dose series of either MCV4 vaccine; however, if MenACWY-D is chosen, administration should be separated from PCV13 by at least four wks [53,76]. If the patient has received one meningococcal vaccination (typically if older than 11 y of age), a two-dose series should be completed if at least eight wks has passed after the first immunization [76]. If the patient has received two doses already, no additional vaccinations are necessary until the booster doses are due [76].

Table 3.

Pediatric Meningococcal Immunization Schedule after Splenectomy

	Age at splenectomy (Use only ONE vaccine product below)
MCV4	8 wks–6 mos	7–23 mos	2–9 y	10–18 y
MenACWY-CRM	2, 4, 6, and 12 mos of age	Two doses ≥12 wks apart with 2^nd dose given after 1 y of age	Two doses ≥8 wks apart	Two doses ≥8 wks apart
MenACWY-D	Not indicated	Not indicated	Two doses ≥8 wks apart	Two doses ≥8 wks apart

	Age at splenectomy (Use only ONE vaccine product below)
MenB	8 wks–6 mos	7–23 mos	2–9 y	10–18 y
MenB-4C	Not indicated	Not indicated	Not indicated	Two doses ≥1 mo apart
MenB-FHbp	Not indicated	Not indicated	Not indicated	Three doses at 0, 1–2, and 6 mos

Note: this table assumes no prior meningococcal immunizations at the time of splenectomy.

MCV4 = quadrivalent meningococcal conjugate vaccine; MenACWY-CRM = quadrivalent meningococcal conjugate vaccine (Menveo); MenACWY-D = quadrivalent meningococcal conjugate vaccine (Menactra); MenB = serogroup B meningococcal vaccine; MenB-4C = serogroup B meningococcal vaccine (Bexsero); MenB-FHbp = serogroup B meningococcal vaccine (Trumenba).

If the first dose of MCV4 is received at less than seven y of age, the first booster should be given three y after completion of the primary series, with additional boosters every five y [72,76]. If the first MCV4 is administered to patients over seven y of age, a booster dose should be given every five y after completion of the primary series [72,76]. Ideally, the entire series would be completed with the same quadrivalent vaccine (MenACWY-CRM or MenACWY-D), but either product may be substituted as needed [72].

Both MenB vaccines are recommended only for use in patients 10 y of age and older [66]. The meningococcal quadrivalent and serogroup B vaccines may be co-administered at different injection sites (e.g., opposite arms) [64, 66]. The same vaccine product (MenB-4C or MenB-FHbp) should be used to complete the MenB series [64, 76].

Hib Vaccination

Like PCV13, Hib is part of the recommended pediatric immunization schedule; therefore, it is important to determine the vaccination history. The number of doses required is based on the history and the patient's age (Table 4). The Hib vaccine is contraindicated in patients younger than 6 wks [76]. Some experts recommend an extra dose of Hib vaccine prior to splenectomy regardless of the age and vaccination history (i.e., even if the patient is up to date on all Hib vaccinations) [53,56].

Table 4.

Pediatric Haemophilus influenzae type B (Hib) Vaccination Schedule after Splenectomy

	Doses of Hib vaccine received prior to 12 mos of age
Age (mos)	Not immunized	1	≥ 2
<12	Refer to CDC Guidelines	Refer to CDC Guidelines	Refer to CDC Guidelines
12–59	2 ≥ 8 wks apart	2 ≥ 8 wks apart (if prior dose received at <12 mos of age)^a	1 ≥ 8 wks after last Hib vaccination (if prior doses received at <12 mos of age)^a
≥60	1^b	Optional	Optional

If prior doses were received after 12 months of age, refer to CDC Guidelines [73].

If a patient has not completed a primary series and booster dose OR received a dose after 14 mos of age, he or she is considered unimmunized [55,73].

Future Trends

Novel approaches to retain splenic function continue to be investigated. Early attempts at autotransplantation (for example, multiple sections of spleen transplanted into the omentum) resulted in complications, such as suppuration, intestinal obstruction, implant torsion, and a higher risk of trauma-related complications (given the lack of bony protection in this region of the body) [77 –79]. However, novel techniques, including the use of smaller units of transplanted splenic tissue and transplantation into different regions of the body, hold the potential to correct many of these shortcoming [80,81].

Conclusion

The mainstays of prevention of fatal post-splenectomy sepsis include education, vaccination, prophylactic antimicrobial therapy in selected patients, and early empirical antimicrobial therapy for febrile episodes. It is critically important to educate patients regarding the lifelong risk of post-splenectomy infection, the importance of vaccinations, and the need for urgent action in response to a febrile episode. Patients should be instructed to notify all of their healthcare professionals about their asplenia and can be provided with information on obtaining a medic alert bracelet or necklace or a splenectomy card.

Footnotes

Author Disclosure Statement

No competing financial interests exist for any of the authors.

References

Wilkins

. The spleen. Br J Haematol, 2002; 117:265–274.

Morris

, Bullock

. The importance of the spleen in resistance to infection. Ann Surg, 1919; 70:513–521.

King

, Shumacker

Jr.

Splenic studies I: Susceptibility to infection after splenectomy performed in infancy. Ann Surg, 1952; 136:239–242.

Diamond

. Splenectomy in childhood and the hazard of overwhelming infection. Pediatrics, 1969; 43:886–889.

Katz

, Pachter

. Indications for splenectomy. Am Surg, 2006; 72:565–580.

Pearson

, McIntosh

, Ritchey

, et al. Developmental aspects of splenic function in sickle-cell diseases. Blood, 1979; 53:358–365.

Di Sabatino

, Carsetti

, Corazza

. Post-splenectomy and hyposplenic states. Lancet, 2011; 378:86–97.

Lutwick

. Infections in asplenic patients. In: Mandell

, Bennett

, Dolin

, editors. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. 7th ed. Philadelphia. Churchill Livingstone Elsevier. 2010:3865–3873.

Centers for Disease Control and Prevention. National Hospital Discharge Survey. Available at: www.cdc.gov/nchs/nhds/nhds_tables.htm#detailed Accessed July 6, 2016.

10.

Centers for Disease Control and Prevention. Sickle Cell Disease. Available at: www.cdc.gov/ncbddd/sicklecell/data.html Accessed July 6, 2016.

11.

Mebius

, Kraal

. Structure and function of the spleen. Nat Rev Immunol, 2005; 5:606–616.

12.

Gao

, Chai

, Dong

, et al. Tuftsin-derived T peptide prevents cellular immunosuppression and improves survival rate in septic mice. Oncotarget, 2016; 7:81791–81805.

13.

Najjar

, Nishioka

. “Tuftsin”: A natural phagocytosis-stimulating peptide. Nature, 1970; 228:672–673.

14.

Pivkin

, Peng

, Karniadakis

, et al. Biomechanics of red blood cells in human spleen and consequences for physiology and disease. Proc Natl Acad Sci USA, 2016; 113:7804–7809.

15.

Sumaraju

, Smith

. Infectious complications in asplenic hosts. Infect Dis Clin North Am, 2001; 15:551–565.

16.

Kruetzmann

, Rosado

, Weber

, et al. Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med, 2003; 197:939–945.

17.

Breukels

, Zandvoort

, van den Dobbelsteen

, et al. Pneumococcal conjugate vaccines overcome splenic dependency of antibody response to pneumococcal polysaccharides. Infect Immun, 2001; 69:7583–7587.

18.

Szendroi

, Miko

, Hajdu

, et al. Splenic autotransplantation after abdominal trauma in childhood: Clinical and experimental data. Acta Chir Hung, 1997; 36:349–351.

19.

Rajani

, Claridge

, Yowler

, et al. Improved outcome of adult blunt splenic injury: A cohort analysis. Surgery, 2006; 140:625–631.

20.

Olufajo

, Rios-Diaz

, Peetz

, et al. Comparing readmissions and infectious complications of blunt splenic injuries using a statewide database. Surg Infect, 2016; 17:191–197.

21.

Gaarder

, Dormagen

, Eken

, et al. Nonoperative management of splenic injuries: Improved results with angioembolization. J Trauma, 2006; 61:192–198.

22.

Schnuriger

, Inaba

, Konstantinidis

, et al. Outcomes of proximal versus distal splenic artery embolization after trauma: A systematic review and meta-analysis. J Trauma, 2011; 70:252–260.

23.

Nakae

, Shimazu

, Miyauchi

, et al. Does splenic preservation treatment (embolization, splenorrhaphy, and partial splenectomy) improve immunologic function and long-term prognosis after splenic injury?. J Trauma, 2009; 67:557–563.

24.

Traub

, Giebink

, Smith

, et al. Splenic reticuloendothelial function after splenectomy, spleen repair, and spleen autotransplantation. N Engl J Med, 1987; 317:1559–1564.

25.

Falimirski

, Syed

, Prybilla

. Immunocompetence of the severely injured spleen verified by differential interference contrast microscopy: The red blood cell pit test. J Trauma, 2007; 63:1087–1091.

26.

Bessoud

, Duchosal

, Siegrist

, et al. Proximal splenic artery embolization for blunt splenic injury: Clinical, immunologic, and ultrasound-Doppler follow-up. J Trauma, 2007; 62:1481–1486.

27.

Tominaga

, Simon

Jr , Dandan

, et al. Immunologic function after splenic embolization: Is there a difference?. J Trauma, 2009; 67:289–295.

28.

Malhotra

, Carter

, Lebman

, et al. Preservation of splenic immunocompetence after splenic artery angioembolization for blunt splenic injury. J Trauma, 2010; 69:1126–1130.

29.

Foley

, Kavnoudias

, Cameron

, et al. Proximal versus distal splenic artery embolisation for blunt splenic trauma: What is the impact on splenic immune function?. Cardiovasc Intervent Radiol, 2015; 38:1143–1151.

30.

Schimmer

, van der Steeg

, Zuidema

. Splenic function after angioembolization for splenic trauma in children and adults: A systematic review. Injury, 2016; 47:525–530.

31.

Theilacker

, Ludewig

, Serr

, et al. Overwhelming postsplenectomy infection: A prospective multicenter cohort study. Clin Infect Dis, 2016; 62:871–878.

32.

Schwartz

, Sterioff

, Mucha

, et al. Postsplenectomy sepsis and mortality in adults. JAMA, 1982; 248:2279–2283.

33.

Schilling

. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med, 1995; 122:187–188.

34.

Bisharat

, Omari

, Lavi

, et al. Risk of infection and death among post-splenectomy patients. J Infect, 2001; 43:182–186.

35.

Holdsworth

, Irving

, Cuschieri

. Postsplenectomy sepsis and its mortality rate: Actual versus perceived risks. Br J Surg, 1991; 78:1031–1038.

36.

Singer

. Postsplenectomy sepsis. Perspect Pediatr Pathol, 1973; 1:285–311.

37.

Weintraub

. Splenectomy: Who, when, and why?. Hosp Pract (Off Ed), 1994; 29:27–34.

38.

Shaw

, Print

. Postsplenectomy sepsis. Br J Surg, 1989; 76:1074–1081.

39.

Bradshaw

, Thomas

Jr.

Regeneration of splenic remnants after partial splenectomy in rats. J Surg Res, 1982; 32:176–181.

40.

Rice

, Oldham

, Hillery

, et al. Clinical and hematologic benefits of partial splenectomy for congenital hemolytic anemias in children. Ann Surg, 2003; 237:281–288.

41.

Seims

, Breckler

, Hardacker

, et al. Partial versus total splenectomy in children with hereditary spherocytosis. Surgery, 2013; 154:849–853.

42.

Moore

, Stevens

, Moore

, et al. Failure of splenic implants to protect against fatal postsplenectomy infection. Am J Surg, 1983; 146:413–414.

43.

Walker

. Splenectomy in childhood: A review in England and Wales, 1960–4. Br J Surg, 1976; 63:36–43.

44.

Brigden

, Pattullo

. Prevention and management of overwhelming postsplenectomy infection: An update. Crit Care Med, 1999; 27:836–842.

45.

Brigden

. Overwhelming postsplenectomy infection still a problem. West J Med, 1992; 157:440–443.

46.

Green

, Shackford

, Sise

, et al. Late septic complications in adults following splenectomy for trauma: A prospective analysis in 144 patients. J Trauma, 1986; 26:999–1004.

47.

Rosner

, Zarrabi

, Benach

, et al. Babesiosis in splenectomized adults. Review of 22 reported cases. Am J Med, 1984; 76:696–701.

48.

Demar

, Legrand

, Hommel

, et al. Plasmodium falciparum malaria in splenectomized patients: Two case reports in French Guiana and a literature review. Am J Trop Med Hyg, 2004; 71:290–293.

49.

Di Cataldo

, Puleo

, Li Destri

, et al. Splenic trauma and overwhelming postsplenectomy infection. Br J Surg, 1987; 74:343–345.

50.

Ram

, Lewis

, Rice

. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev, 2010; 23:740–780.

51.

Gaston

, Verter

, Woods

, et al. Prophylaxis with oral penicillin in children with sickle-cell anemia: A randomized trial. N Engl J Med, 1986; 314:1593–1599.

52.

Knight-Madden

, Serjeant

. Invasive pneumococcal disease in homozygous sickle cell disease: Jamaican experience 1973–1997. J Pediatr, 2001; 138:65–70.

53.

American Academy of Pediatrics. Red Book: 2015 report of the Committee on Infectious Diseases. Kimberlin

, Brady

, Jackson

, et al., editors. American Academy of Pediatrics. 2015.

54.

Falletta

, Woods

, Verter

, et al. Discontinuing penicillin prophylaxis in children with sickle cell anemia: Prophylactic Penicillin Study II. J Pediatr, 1995; 127:685–690.

55.

Centers for Disease Control and Prevention. Pneumococcal disease. 2015. In: Epidemiology and Prevention of Vaccine-Preventable Diseases [Internet]. Washington D.C. Public Health Foundation. 13. Available at: www.cdc.gov/vaccines/pubs/pinkbook/pneumo.html

56.

Briere

, Rubin

, Moro

, et al. Prevention and control of Haemophilus influenzae type b disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep, 2014; 63(RR-01):1–14.

57.

Shatz

, Schinsky

, Pais

, et al. Immune responses of splenectomized trauma patients to the 23-valent pneumococcal polysaccharide vaccine at 1 versus 7 versus 14 days after splenectomy. J Trauma, 1998; 44:760–765.

58.

Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep, 2012; 61:816–819.

59.

Kobayashi

, Bennett

, Gierke

, et al. Intervals between PCV13 and PPSV23 vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep, 2015; 64:944–947.

60.

Food and Drug Administration. Vaccines and Related Biological Products Advisory Committee (VRBPAC) Adult Indication Briefing Document: Prevnar 13. In: US Department of Health and Human Services, Food and Drug Administration, editor. Silver Spring, MD. 2011.

61.

Jackson

, Gurtman

, van Cleeff

, et al. Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older. Vaccine, 2013; 31:3594–3602.

62.

Papadatou

, Orthopoulos

, Theodoridou

, et al. Long-lasting hyporesponsivenss induced by the 23-valent pneumococcal polysaccharide vaccine (PPV23) in asplenic patients with beta-thalassemia major. Vaccine, 2015; 33:3779–3783.

63.

Sigurdardottir

, Center

, Davidsdottir

, et al. Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children. Vaccine, 2014; 32:417–424.

64.

MacNeil

, Rubin

, McNamara

, et al. Use of MenACWY-CRM vaccine in children aged 2 through 23 months at increased risk for meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices, 2013. MMWR Morb Mortal Wkly Rep, 2014; 63:527–530.

65.

Centers for Disease Control and Prevention. Recommendation of the Advisory Committee on Immunization Practices (ACIP) for use of quadrivalent meningococcal conjugate vaccine (MenACWY-D) among children aged 9 through 23 months at increased risk for invasive meningococcal disease. MMWR Morb Mortal Wkly Rep, 2011; 60:1391–1392.

66.

Folaranmi

, Rubin

, Martin

, et al. Use of serogroup B meningococcal vaccines in persons aged >/ = 10 years at increased risk for serogroup B meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep, 2015; 64:608–612.

67.

Kim

, Riley

, Harriman

, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older – United States, 2017. MMWR Morb Mortal Wkly Rep, 2017; 66:136–138.

68.

Gossger

, Snape

, Yu

, et al. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: A randomized controlled trial. JAMA, 2012; 307:573–582.

69.

Vesikari

, Esposito

, Prymula

, et al. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: Results of two randomised trials. Lancet, 2013; 381:825–835.

70.

Findlow

, Bai

, Findlow

, et al. Safety and immunogenicity of a four-component meningococcal group B vaccine (4CMenB) and a quadrivalent meningococcal group ACWY conjugate vaccine administered concomitantly in healthy laboratory workers. Vaccine, 2015; 33:3322–3330.

71.

Pfizer, Inc.. Pfizer announces positive top-line results of a Phase 2 study of Trumenba (meningococcal group B vaccine) co-administered with routine meningococcal (A, C, Y, and W) and tetanus, diphtheria and pertussis (Tdap) vaccines in adolescents. Available at: www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_positive_top_line_results_of_a_phase_2_study_of_trumenba_meningococcal_group_b_vaccine_co_administered_with_routine_meningococcal_a_c_y_and_w_and_tetanus_diphtheria_and_pertussis_tdap_vaccines_in Accessed Dec 7, 2015.

72.

Cohn

, MacNeil

, Clark

, et al. Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep, 2013; 62(RR-2):1–28.

73.

Immunization Action Coalition. Meningococcal Disease. Available at: www.immunize.org/askexperts/experts_men.asp Accessed Jan 10, 2017.

74.

Nuorti

, Whitney

. Prevention of pneumococcal disease among infants and children – Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine – Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep, 2010; 59(RR-11):1–18.

75.

Rubin

, Levin

, Ljungman

, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis, 2014; 58:309–318.

76.

Robinson

, Romero

, Kempe

, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger – United States, 2017. MMWR Morb Mortal Wkly Rep, 2017; 66:134–135.

77.

Di Carlo

, Toro

. Splenic autotransplantation is always valid after splenectomy. J Invest Surg, 2017; Jan 3:1–2.

78.

Di Carlo

, Pulvirenti

, Toro

. A new technique for spleen autotransplantation. Surg Innov, 2012; 19:156–161.

79.

Holdsworth

. Regeneration of the spleen and splenic autotransplantation. Br J Surg, 1991; 78:270–278.

80.

Grunewald

, Rezende

, Figueiredo

, et al. Autotransplantation of spleen mitigates drug-induced liver damage in splenectomized mice. J Invest Surg, 2016; Nov 30:1–8. Epub ahead of print.

81.

Karip

, Mestan

, Isik

, et al. A solution to the negative effects of splenectomy during colorectal trauma and surgery: An experimental study on splenic autotransplantation to the groin area. BMC Surg, 2015; 15:129–136.