Prevention and therapy of bacterial infections for children with asplenia or hyposplenia

Abstract

The asplenic state, whether functional or anatomic, is associated with an increased risk of life threatening infection or postsplenectomy sepsis (PSS). Because the risk of bacteremia with encapsulated bacteria is enhanced in children with asplenia, vaccination to prevent infection by Streptococcus pneumoniae, Haemophilus influenzae type b (Hib) and Neiserria meningitidis is recommended. Despite the increasing prevalence of penicillin-resistant S pneumoniae, prophylactic penicillin use is also recommended for children with asplenia who are younger than five years of age, and for at least one year following splenectomy. Continuation of antibiotic prophylaxis beyond these times depends on individual clinical circumstances and the prevalence of penicillin-resistant S pneumoniae in the community. When children with asplenia develop fever or nonspecific symptoms, they should be assessed immediately. If bacterial sepsis is suspected, blood and other appropriate body fluids should be cultured, and treatment should begin immediately with parenteral broad spectrum antibiotics that are also effective against the strains of S pneumoniae circulating in the community. In children with asplenia with overwhelming S pneumoniae bacteremia, the mortality rate is high, even with prompt initiation of appropriate antibiotic therapy. Thus, preventive measures are important.

The asplenic state, whether functional or anatomic, is associated with an increased risk of life threatening bacterial infection or postsplenectomy sepsis (PSS) (1–10). Compared with the incidence in healthy children (children who are generally well and have not had a splenectomy), the incidence of mortality from septicemia is increased 50-fold in children who have had splenectomy following trauma, and approximately 350-fold in children with hemoglobinopathies (sickle cell disease or thalassemia) (11). The risk of sepsis is greatest among individuals (children and adults) who have congenital asplenia or functional asplenia associated with sickle cell anemia. It is also relatively elevated following splenectomy for idiopathic thrombocytopenia, acquired hemolytic anemia, Hodgkin’s disease and other hematological disorders (11). The risk of bacterial sepsis is higher in younger children than in older children. It is highest during the initial year following splenectomy, but the increased risk compared with the general population persists for life. The risk of sepsis is relatively lower in children following splenectomy for trauma (11).

The spleen plays an important role in the body’s defense against infection. It filters antigen and antibody complexes and bacteria. The spleen is particularly important in removing bacteria that are not well opsonized from circulation. As well, it is an important site for immunoglobulin M production, antigen presentation to T cells and memory B cell differentiation. The lack of such functions when the spleen is absent or not functioning properly explains the increased susceptibility to bacterial infections (12–21). Decreased properdin levels (22) and diminished alternative complementary pathway activity (23) have been reported in individuals who have undergone splenectomies. The human spleen is the production site of a peptide that promotes phagocytosis (24), and absence of this substance further compromises the person with asplenia.

The life threatening bacteremia or meningitis that occurs in individuals with asplenia is primarily caused by polysaccharide encapsulated bacteria. Pneumococci are the predominant pathogens responsible for PSS, with death occurring in 50% to 70% of these patients. Haemophilus influenzae type b (Hib) and Neiserria meningitidis are isolated with increased frequency. Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli and Salmonella species are also of concern, but are relatively less common causes of bacteremia in these patients. Other less common bacterial infections may occur in association with asplenia. For example, individuals with asplenia are at increased risk of acquiring bacteremia after dog bites from organisms that colonize the mouths of dogs such as capnocytophaga.

The purpose of this statement is to provide recommendations for a standardized approach to the care of children with functional or anatomic asplenia as follows. Suggestions are presented for patient and family education. Recommendations are made regarding vaccines to prevent bacterial infection. Guidance is provided regarding the use of chemoprophylaxis in an era when antibiotic resistance is increasingly prevalent. Emphasis is placed on the close medical observation of children with asplenia with fever and on aggressive treatment with antibiotics for suspected infection.

PATIENT AND FAMILY EDUCATION

Although bacterial vaccines and prophylactic antibiotics are effective, they neither cover all conditions nor provide complete protection. Therefore, children with asplenia and their families must be educated to notify their physicians promptly about any signs or symptoms of an infection, even ‘minor’ symptoms such as those associated with upper respiratory tract infections. Both the patient and the family need to be aware that individuals with asplenia are at increased risk of severe illness due to bacterial infection throughout their lives.

The patient and family members should be advised that recognition of PSS can often be difficult because the onset may be insidious. However, death may occur in a matter of hours. The importance of using prophylactic antibiotics and bacterial vaccines correctly should be emphasized repeatedly. Health care professionals should advise their patients to wear a Medic Alert bracelet. Patients should also be provided with a medical card indicating recommended immunizations, the need for prophylactic antibiotics, the risk of PSS and the importance of establishing a plan for medical emergencies. When travelling, children with asplenia should carry a letter from their physician stating their diagnosis, associated risks and a suggested medical management plan should they become ill. They should also carry a supply of penicillin (or suitable alternative if they are allergic to penicillin and/or other antibiotics); if they develop fever or are unable to obtain prompt medical attention for any reason, they should take the medication immediately and seek medical attention as soon as possible (25,26).

BACTERIAL VACCINES

Because the risk of bacteremia is higher in children with asplenia, several bacterial vaccines are recommended (Table 1). The responses of individuals with asplenia to each vaccine are generally sufficient to provide some protection. The antibody response in children with asplenia to polysaccharide vaccines, such as pneumococcal and meningococcal vaccines, may not be comparable with that of normal children. As a result, repeated immunization may be necessary. When elective splenectomy is to be performed, these vaccines should be given at least two weeks before the operation, if possible, to increase the likelihood of a protective antibody response. These vaccines can be given concurrently at separate injection sites when necessary.

TABLE 1:

Recommendations for immunization and prophylactic antimicrobial agents in children with asplenia

Age	Immunization	Prophylactic antibiotic
Birth to two years	Hib conjugate vaccine at two, four and six months of age; booster at 15 to 18 months of age Consider influenza vaccine annually for children older than six months of age	TMP/SMX (5 mg TMP/25 mg SMX/kg/day) once a day for infants younger than six months of age; penicillin 125 mg orally bid for infants older than six months of age
Two to five years	Hib vaccine, if not given previously Pneumococcal vaccine Quadrivalent meningococcal polysaccharide vaccine Consider influenza vaccine annually	Penicillin 125 mg orally bid or amoxicillin (20 mg/kg/day, maximum 500 mg/day) orally bid or bacampicillin (25 to 50 mg/kg/day, maximum 800 mg/day) orally bid or pivampicillin (40 mg/kg/day, maximum 350 mg/day for children younger than four years of age, maximum 525 mg for children older than four years and younger than 6 years of age) orally bid
Five years to adolescence	Hib vaccine, if not given previously Pneumococcal vaccine, if not given previously. If given before five years of age, then give first booster dose three years after the initial vaccination; otherwise, repeat vaccination once, five years after the initial vaccination Quadrivalent meningococcal polysaccharide vaccine, if not given previously Consider influenza vaccine annually	Penicillin 250 mg orally bid or amoxicillin 250 mg bid orally or bacampicillin 400 mg bid orally or pivampicillin (40 mg/kg/day, maximum 525 mg/day if the child is younger than seven years of age, otherwise maximum 700 mg/day)

Hib Haemophilus influenzae type b; TMP/SMX Trimethoprim/sulfamethoxazole

The unconjugated polysaccharide-based 23-valent pneumococcal vaccine, the only one currently available, should be given to children at two years of age or older (27,28). Revaccination is recommended three years later for children who were immunized when they were younger than five years of age, and five years later for older children. Additional vaccine boosters are not recommended. Recommendations will undoubtedly change once conjugated pneumococcal vaccines are available. These conjugated pneumococcal vaccines are expected to provide better protection because they are effective during the first two years of life.

Immunization with a Hib-conjugated vaccine should be initiated in infancy, as is recommended for healthy children (28,29). Older children and adults who have not received a Hib vaccine may also benefit from this vaccine. For older children and adults, only a single dose is required.

Although meningococcal sepsis after splenectomy is rare, administration of quadrivalent meningococcal polysaccharide vaccine against N meningitidis (groups A, C, Y and W-135) is recommended for children with asplenia who are two years of age and older (25,28). The meningococcal vaccine does not provide prolonged protection, and is ineffective against serogroup B, which is common in any age group. Booster doses are not recommended routinely but should be considered in situations of increased risk of exposure, such as during epidemics.

CHEMOPROPHYLAXIS

Individuals with asplenia who are receiving prophylactic antibiotics have been shown to have a decreased incidence of PSS (30). The pathogens of greatest concern include coliform bacilli during the child’s first three months of life and pneumococcus after the first three months. Hib vaccines have resulted in a marked decline in Hib disease in the general population. Given the adequate immune response of children with asplenia to the conjugated Hib vaccine, one would expect that individuals with asplenia or hyposplenia have substantial protection against disease. Because vaccination is only a partial solution to the problem, daily antimicrobial prophylaxis is recommended for children with asplenia (5). This recommendation is based on a study of children with sickle cell disease (31). In these children, oral penicillin V (125 mg twice daily) reduced the incidence of severe bacterial infection by 84% in comparison with children who received placebo. Though the efficacy of prophylactic antibiotics has been proven only in children with sickle cell disease, it is recommended that all children with asplenia receive prophylactic antibiotics (Table 1) (27,28).

The duration of prophylaxis is controversial. Most experts in infectious diseases agree that continued prophylaxis is indicated in children up to five years of age. In children who become asplenic after five years of age, prophylactic antibiotics should be given for at least one year after splenectomy. Some experts in infectious diseases recommend continued prophylaxis throughout childhood and into adulthood. Studies show the emergence of penicillin resistance in pneumococci worldwide; penicillin resistance occurs more commonly in individuals who received antibotic prophylaxis (32). Because patients with asplenia who receive continuous penicillin treatment are at risk of acquiring antibiotic-resistant pneumococci, alternative approaches need to be considered. The development of improved techniques to assess splenic function in children with hyposplenism and those in whom partial splenectomies have been performed may allow chemoprophylaxis to be safely discontinued.

For antimicrobial prophylaxis, oral penicillin V (125 mg twice daily for children younger than five years of age and 250 mg twice daily for children five years of age and older) is recommended. Alternatively, amoxicillin, bacampicillin or pivampicillin are acceptable alternative agents. For children younger than six months of age with congenital asplenia, E coli is a concern; therefore, trimethoprim/sulfamethoxazole (5 mg TMP/25 mg SMX/kg once a day) is the preferred agent. If a penicillin allergy is considered to be likely, the child should be referred to an allergist to verify the diagnosis and help select an alternative agent. Alternative antibiotics may be necessary in communities with a high prevalence of penicillin-resistant S pneumoniae.

ASPLENIC CHILDREN WITH FEVER OR ACUTE ILLNESS

Polyvalent pneumococcal vaccine, Hib conjugate vaccine and prophylactic antibiotics reduce but do not eliminate the risk of sepsis in children with hyposplenia (33). Therefore, when fever (even low grade fever) or nonspecific symptoms develop, they should be assessed immediately with a physical examination. When bacterial sepsis is suspected, blood and other appropriate body fluids should be cultured, and treatment should begin immediately with parenteral antibiotics such as cefotaxime, ceftriaxone or other antibiotics effective against S pneumoniae, Hib and N meningitidis. In the seriously ill patient who has been taking penicillin prophylactically, consider adding vancomycin to cefotaxime or ceftriaxone to provide coverage for multiply antibiotic-resistant pneumococcal isolates until susceptibility patterns are known. For patients who present with overwhelming S pneumoniae bacteremia, the mortality rate is high, even with prompt initiation of appropriate antibiotic therapy. Therefore, preventive measures remain important.

RECOMMENDATIONS

• The Canadian Paediatric Society (CPS) recommends that physicians educate patients and families about the risks associated with asplenia and hyposplenia, the preventive measures that can be taken, and interventions that are necessary when a child develops a febrile illness.

• The CPS recommends that in addition to routine childhood immunizations, all children with asplenia and hyposplenia receive vaccines to protect against S pneumoniae and N meningitidis at the appropriate ages, and that an influenza vaccine be offered yearly.

• Despite the increasing prevalence of penicillin-resistant S pneumoniae, the CPS recommends that prophylactic antibiotics continue to be used for children diagnosed with asplenia and hyposplenia who are younger than five years of age, and for at least one year following splenectomy. Continuation of antibiotics beyond this time depends on the child’s individual clinical circumstances.

• The CPS recommends that, despite the use of prophylactic antibiotics and/or vaccines, children with asplenia or hyposplenia be considered at high risk of serious bacterial infection and, thus, be closely monitored for febrile illness, promptly assessed for infectious causes when fever occurs, and receive aggressive antimicrobial therapy whenever an infection is suspected.