Chapter 57. Infections in Asplenic Children

Long thought of as an unessential organ that could be removed without adverse effects, the spleen and its significance in defense against infections were not well recognized until 1952, when King and Shumacker published a seminal paper describing an association between splenectomy and subsequent susceptibility to overwhelming infection.1 Since then, severe infection in asplenic individuals has become a well-known entity, termed postsplenectomy sepsis or overwhelming post-splenectomy sepsis. This chapter will provide an overview of the basic functions of the spleen and the infectious complications associated with asplenia.

Causes of Asplenia

A child may be asplenic for anatomic or functional reasons. Anatomic reasons include: (1) congenital asplenia, which can be isolated, or part of Ivemark syndrome, which is associated with cardiovascular defects and heterotaxy and (2) splenectomy. Splenectomy may be performed for various reasons. In children, the most common reasons are trauma-associated splenic rupture, malignancy, hypersplenism, and splenomegaly associated with persistent anemia and/or thrombocytopenia.2 Functional asplenia results from having an anatomically intact but poorly working spleen. There are various conditions that can cause functional asplenia, including sickle cell disease (Table 57–1). Some of the mechanisms leading to functional asplenia include infarction, infiltration, and impaired phagocyte function.2–4

Epidemiology

Rates of overwhelming infection in asplenic children vary, depending on age and underlying reason for asplenia. Past studies have found that younger age, underlying illnesses including hemoglobinopathies, and splenectomy within the prior 3 years are associated with increased risk.2,5,6 However, it is important to note that there is a lifelong risk for overwhelming infection.

Anatomy

The spleen is comprised of a fibrous capsule, a trabecular framework of fibers and smooth muscle, cell-rich red and white pulp interspersed among this framework, and a blood supply arising from the splenic artery2,7,8:

• Fibrous capsule: The splenic capsule is highly elastic, containing smooth muscle that allows for the distension and splenomegaly seen in many pathologic states.
• White pulp: White pulp contains aggregates of lymphoid follicles (B-lymphocytes) found in the periarterial sheaths of the medium-sized splenic arteries. These follicles can form germinal centers with antigenic stimulation. At the edge of each follicle is a region called the marginal zone, where antigen trapping and processing occur.
• Red pulp: Red pulp is composed of venous sinusoids and splenic cords with reticular cells, macrophages, neutrophils, and elements of circulating blood. Blood flows through the red pulp via open circulation or closed circulation. Approximately 90% of the spleen's blood supply travels through open circulation via the venous sinusoids, a slower route allowing for filtration of the blood.
• Blood supply: The splenic artery divides into many branches prior to entering the hilum of the spleen as the trabecular artery. This arterial network is surrounded by periarterial sheaths and continues to divide, eventually ending as arterioles in the red pulp.

Normal Functions of the Spleen

Immune Response

The main immune functions of the spleen include antigen processing, antibody production, and phagocytosis.2,4,8 Antigens are trapped and processed in the marginal zone, which contains T-lymphocytes and macrophages. From there, the antigen moves into the germinal center of the lymphoid follicle where B-lymphocytes are activated and become memory B cells and plasma cells. The plasma cells then travel to the red pulp and release antibody into the blood. Although liver macrophages are very efficient at clearing opsonized blood-borne bacteria, splenic macrophages are better at responding to bacteria with little or no opsonic coating, such as the encapsulated organisms.3,8 In addition to the immune functions mentioned above, the spleen is capable of making the alternate complement component properdin and other opsonins, such as tuftsin.

Hematopoiesis

The spleen plays an active role in hematopoiesis in the second and third trimesters of fetal development. Although not a normal site for hematopoiesis after birth, it can become active in certain disease states in which extramedullary hematopoiesis occurs. Examples include the thalassemias, myelofibrosis, and certain tumors such as hemangiomas, hepatoblastomas, and leiomyomas.8

Filtration

Apart from its responsibility to remove microorganisms and immune complexes from the circulation, the spleen also plays a role in the removal or repair of damaged erythrocytes.4,8 Deformed cells are removed by macrophages, a process known as culling, and cells containing particulate material, such as Howell-Jolly bodies, Heinz bodies, or vesicles, undergo a process known as pitting. Pitting occurs when macrophages remove the particulate material and the erythrocyte subsequently returns to the normal circulation.

Storage

Platelets, granulocytes, and factor VIII are stored in the spleen. Normally, up to 30–40% of the body's platelets are stored in the spleen. This percentage can increase greatly in pathologic states, resulting in severe thrombocytopenia. Additionally, the spleen can hold up to 45% of the body's erythrocyte mass in pathologic states such as splenic sequestration associated with sickle cell disease.2

Why Infections Occur with Asplenia

In the child with asplenia or functional asplenia, there is impaired antigen recognition, impaired production of antibodies (namely antigen specific IgM), altered T cell function, and altered phagocytic activity with impaired removal of particles unable to be compensated by liver and lung macrophages.8–10 This leads to an increased risk of infection, especially with encapsulated microorganisms.

History and Physical Examination

Symptoms are usually nonspecific. A child may present with a short prodrome of fever, chills, and other complaints such as malaise, myalgias, sore throat, headache, nausea, vomiting, diarrhea, and/or abdominal pain. He or she initially may appear nontoxic, but then rapidly progress to a more classical septic picture, with respiratory distress, cardiovascular instability, disseminated intravascular coagulation, purpura fulminans, hypoglycemia, or coma within hours of presentation.2,3,11–15 In many cases, there is no identifiable focus of infection. When a defined infectious focus is found, meningitis and pneumonia are common.1,13

Sepsis should always be suspected, worked up, and empirically treated when faced with a febrile or ill-appearing child with a history of asplenia. While many other etiologies may explain the child's constellation of symptoms, it is important to address this potentially fatal cause first. Many organisms may cause infections in asplenic children; however, certain ones occur more frequently and should be kept in mind:

• Most Common Organisms Associated with Infections in Asplenic Children
  • Streptococcus pneumoniae: The most commonly identified organism, accounting for 50–90% of septic episodes.16,17 However, the incidence of invasive pneumococcal disease may be decreasing. A recent study by Halasa et al. noted a marked decrease in the incidence of invasive pneumococcal disease among children with sickle cell disease after the introduction of routine immunization with the pneumococcal conjugate vaccine.18
  • Haemophilus influenzae type b: The second most common organism, although invasive disease is rare now with the use of the Hib vaccine.
  • Neisseria meningitidis: The third most common organism. It can be associated with fulminant sepsis.
• Other Organisms
  • Capnocytophaga canimorsus: A gram-negative rod that is usually acquired following close contact with dog or cat saliva.
  • Babesia species: Asplenic individuals are a greater risk for morbidity and mortality secondary to babesiosis.
  • Plasmodium species: Malarial parasite clearance is delayed in asplenic individuals.19
  • Escherichia coli
  • Klebsiella species
  • Staphylococci
  • Other Streptococci (i.e., Streptococcus suis, Streptococcus bovis)
  • Salmonella species
  • Bordetellaholmesii: A rare gram-negative rod associated with bacteremia, endocarditis, and respiratory illness in humans, it has been isolated from asplenic individuals in the past.14,20

General Evaluation

When faced with a febrile, asplenic child in the outpatient setting, a preliminary workup may be initiated if the situation permits (Figure 57–1). Following a thorough history and physical, preliminary diagnostic testing should include a complete blood count with differential (look for organisms on the peripheral smear) and a blood culture. Other tests to consider are urinalysis with microscopy, urine culture, cerebrospinal fluid studies and culture, stool studies such as bacterial culture, assay for Clostridium difficile toxin if the child has been on prophylactic antibiotics, and assays for adenovirus and rotavirus, viral studies to help determine the etiology of the child's fever should a bacterial etiology be ruled out, and chest radiograph, if indicated based on age, symptoms, and physical examination findings. Ideally, bloodwork should be drawn prior to the administration of antibiotics. However, the diagnostic workup should never delay empiric therapy.

Empiric Therapy

(Tables 57–2 and 57–3)

In general, empiric therapy should be targeted toward the most common organisms associated with asplenia. In the outpatient setting, an empiric dose of antibiotics should be given prior to transferring the child to an emergency department or inpatient facility. If the child is in a location far from any medical provider or medical center, primary caretakers should be instructed to give the child a dose of oral antibiotics immediately. Efforts should be made to ensure that families always keep the antibiotic on hand.

Targeted Therapy

Once an organism is identified, more targeted therapy can be initiated. Therapeutic decisions should be based on the child's clinical status, organism identification, and antibiotic susceptibility pattern.

Chemoprophylaxis

Chemoprophylaxis against pneumococcal infections is recommended for most children with asplenia, such as those with congenital asplenia, sickle cell disease, splenectomy secondary to hemolytic anemias, malignancies, liver transplants, and during the first year following splenectomy for any reason.21,22 Chemoprophylaxis is also recommended for children younger than 5 years of age with asplenia for any reason. In the United States, the duration of chemoprophylaxis may vary with the underlying reason for being asplenic. Chemoprophylaxis is recommended during the first year following splenectomy at any age. For other children, the recommendation for continuing chemoprophylaxis until the age of five is based on past experience with sickle cell disease in which the risk for development of pneumococcal bacteremia or meningitis may be lower in school-aged children.23

Prophylactic regimens may include the following:

• Penicillin VK 125 mg PO bid for children < 5 years
• Penicillin VK 250 mg PO bid for children ≥ 5 years
• Amoxicillin 20 mg/kg/day
• Trimethoprim/sulfamethoxazole (TMP/SMX) 5 mg TMP/kg PO daily for those with penicillin allergies (based on dosing for Pneumocystis jiroveci prophylaxis). Higher rates of pneumococcal resistance with TMP/SMX have been reported.24

Primary caretakers and patients should be informed that chemoprophylaxis does not guarantee complete protection against infection. Regarding dental procedures, there are no current recommendations regarding prophylaxis for those no longer on daily chemoprophylaxis without cardiac conditions.25,26

Vaccinations

Vaccines are not contraindicated. Children should be vaccinated according to the schedule recommended by the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians with appropriate modifications for children with asplenia as emphasized below. An updated schedule may be found on the following Web site provided by the Centers for Disease Control and Prevention: http://www.cdc.gov/vaccines/recs/schedules. Recommended vaccines for asplenic children include the following (see Tables 57–4 to 57–5)22,27–29:

• Pneumococcal conjugate and/or polysaccharide vaccine. In addition to receiving their primary and booster series, asplenic children should be revaccinated as recommended in Table 57–5 since they continue to remain at a greater risk for overwhelming pneumococcal sepsis.
• H. influenzae type b vaccine. Severe infection with H. influenzae type b, seen frequently prior to the advent of the vaccine, is now rare, although still possible.
• Meningococcal polysaccharide or conjugate vaccine. Asplenic children as young as 2 years of age should be given the meningococcal polysaccharide vaccine (MPSV), as opposed to the meningococcal conjugate vaccine (MCV), which should be given at 11–12 years of age. Revaccination should be considered given the continued risk for meningococcal disease.29 Of note, although it is not approved currently for use in younger children, the recommendations regarding use of MCV may change in the future.
• Influenza vaccine. Although not specifically indicated for asplenia, it is a recommended vaccine which may be important for those with asplenia as influenza can be associated with bacterial coinfection, especially with Staphylococcus aureus, S. pneumoniae, and N. meningitidis.

Education

Primary caretaker and patient education are crucial in helping to prevent severe infections. Studies have indicated that many patients and their caretakers are not well informed about the risk for infection and the importance of chemoprophylaxis, vaccination, and/or empiric therapy.30–32 In addition, those who are not well informed may be less likely to seek medical care in a timely fashion. The risk of severe infection with asplenia and the need for the preventive measures mentioned previously should be discussed repeatedly.11,33 Emphasis should be placed on the need to seek medical attention at the start of any illness as the progression to fulminant sepsis can be rapid. Medical care should also be sought with any animal or human bites.34 All health care professionals should be made aware of the child's diagnosis. The use of medical alert bracelets, portable immunization records, or portable cards outlining steps for what to do in the case of illness have also been suggested.16,35,36

Individuals with asplenia are at risk for overwhelming infections. Asplenic children are at greater risk for overwhelming sepsis than their adult counterparts. Preventive measures and timely medical care are crucial in averting serious morbidity and mortality. Main points to keep in mind when caring for an asplenic child are the following:

• Chemoprophylaxis: An important measure in preventing invasive pneumococcal disease in children with asplenia, although breakthrough infection can still occur, especially with penicillin-resistant strains.
• Education: Emphasis on the risk for infection and the need to seek early medical attention should occur on routine basis.
• Diagnosis and treatment: Never let the diagnostic workup delay empiric therapy.