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Late Effects of Treatment for Childhood Cancer (PDQ®)

Late Effects of the Immune System

Late effects of the immune system have not been well studied, especially in survivors treated with contemporary therapies. Reports published about long-term immune system outcomes are limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment.


Surgical or functional splenectomy increases the risk of life-threatening invasive bacterial infection:[1]

  • Although staging laparotomy is no longer standard practice for pediatric Hodgkin lymphoma, patients from earlier time periods have ongoing risks.[2,3]
  • Children may be rendered asplenic by radiation therapy to the spleen in doses greater than 30 Gy.[4,5] Low-dose involved-field radiation therapy (21 Gy) combined with multiagent chemotherapy did not appear to adversely affect splenic function, as measured by pitted red blood cell assays.[5] No other studies of immune status after radiation therapy are available.
  • Functional asplenia (with Howell-Jolly bodies, reduced splenic size and blood flow) after hematopoietic stem cell transplantation (HSCT) has been attributed to graft-versus-host disease (GVHD).

Individuals with asplenia, regardless of the reason for the asplenic state, have an increased risk of fulminant bacteremia, especially associated with encapsulated bacteria, which is associated with a high mortality rate. The risk of bacteremia is higher in younger children than in older children, and this risk may be greater during the years immediately after splenectomy. Fulminant septicemia, however, has been reported in adults up to 25 years after splenectomy.

Bacteremia may be caused by the following organisms:

  • Streptococcus pneumoniae. The most common pathogen that causes bacteremia in children with asplenia.
  • Other streptococci.
  • Haemophilus influenzae type b (Hib).
  • Neisseria meningitidis.
  • Escherichia coli; Staphylococcus aureus.
  • Gram-negative bacilli, such as the Salmonella species, the Klebsiella species, and Pseudomonas aeruginosa.

Individuals with functional or surgical asplenia are also at increased risk of fatal malaria and severe babesiosis.

Posttherapy management

Two primary doses of quadrivalent meningococcal conjugate vaccine should be administered 2 months apart to children with asplenia, from age 2 years through adolescence, and a booster dose should be administered every 5 years.[6] (Refer to the Scheduling Immunizations section of the Red Book for more information.) However, the efficacy of meningococcal vaccines in children with asplenia has not been established. (Refer to the Meningococcal Infections section of the Red Book for more information.) No known contraindication exists to giving these vaccines at the same time as other required vaccines, in separate syringes, at different sites.

Pneumococcal conjugate vaccine (PCV) and pneumococcal polysaccharide vaccine (PPSV) are indicated at the recommended age for all children with asplenia. Following the administration of the appropriate number of doses of PCV13, PPSV23 should be administered starting at age 24 months. A second dose should be administered 5 years later. For children aged 2 to 5 years with a complete PCV7 series who have not received PCV13, a supplemental dose of PCV13 should be administered. For asplenic individuals aged 6 to 18 years who have not received a dose of PCV13, a supplemental dose of PCV13 should be considered.[7] (Refer to the Pneumococcal Infections section of the Red Book for more information.) Hib immunization should be initiated at age 2 months, which is recommended for otherwise healthy young children and for all previously unimmunized children with asplenia.[7] (Refer to the Scheduling Immunizations section of the Red Book for more information.)

Daily antimicrobial prophylaxis against pneumococcal infections is recommended for many children with asplenia, regardless of their immunization status. Although the efficacy of antimicrobial prophylaxis has been proven only in patients with sickle cell anemia, other children with asplenia at particularly high risk, such as children with malignant neoplasms or thalassemia, should also receive daily chemoprophylaxis. In general, antimicrobial prophylaxis (in addition to immunization) should be considered for all children with asplenia younger than 5 years and for at least 1 year after splenectomy.

The age at which chemoprophylaxis is discontinued is often an empiric decision. On the basis of a multicenter study, prophylactic penicillin can be discontinued at age 5 years in children with sickle cell disease who are receiving regular medical attention and who have not had a severe pneumococcal infection or surgical splenectomy. The appropriate duration of prophylaxis is unknown for children with asplenia attributable to other causes. Some experts continue prophylaxis throughout childhood and into adulthood for particularly high-risk patients with asplenia.

Table 12. Spleen Late Effectsa
Predisposing Therapy Immunologic Effects Health Screening/Interventions
GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation; IgA = immunoglobulin A; T = temperature.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Radiation impacting spleen; splenectomy; HSCT with currently active GVHD Asplenia/hyposplenia; overwhelming post-splenectomy sepsis Blood cultures during febrile episodes (T >38.5°C); empiric antibiotics
HSCT with any history of chronic GVHD Immunologic complications (secretory IgA deficiency, hypogammaglobulinemia, decreased B cells, T cell dysfunction, chronic infections [e.g., conjunctivitis, sinusitis, and bronchitis associated with chronic GVHD]) History: chronic conjunctivitis, chronic sinusitis, chronic bronchitis, recurrent or unusual infections, sepsis
Exam: attention to eyes, nose/sinuses, and lungs

Refer to the Centers for Disease Control and Prevention (CDC) Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients for more information on posttransplant immunization.

Humoral Immunity

Although the immune system appears to recover from the effects of active chemotherapy and radiation therapy, there is some evidence that lymphoid subsets may not always normalize. Innate immunity, thymopoiesis, and DNA damage responses to radiation were shown to be abnormal in survivors of childhood leukemia.[8] Antibody levels to previous vaccinations are also reduced in patients off therapy for acute lymphoblastic leukemia for at least 1 year,[9,10] suggesting persistence of abnormal humoral immunity [11] and a need for revaccination in such children. Many survivors of childhood cancer will remain susceptible to vaccine-preventable infections.

While there is a paucity of data regarding the benefits of administering active immunizations in this population, reimmunization is necessary to provide protective antibodies. The recommended reimmunization schedule will depend on previously received vaccinations and on the intensity of therapy.[12,13] In some children who received intensive treatment, consideration may be given to evaluating the antibodies against common vaccination antigens to determine the need for revaccination. (Refer to the Scheduling Immunizations section of the Red Book for more information.)

Immune status is also compromised after HSCT, particularly in association with GVHD.[14] In a prospective, longitudinal study of 210 survivors treated with allogeneic HSCT, antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95.7%), rubella (92.3%), poliovirus (97.9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%). However, responses to pertussis (25.0%), measles (66.7%), mumps (61.5%), hepatitis B (72.9%), and diphtheria in tetanus-diphtheria (Td) recipients (48.6%) were less favorable. Factors associated with vaccine failure include older age at immunization; lower CD3, CD4, or CD19 count; higher immunoglobulin M concentration; positive recipient cytomegalovirus serology; negative titer before immunization; history of acute or chronic GVHD; and radiation conditioning.[15]

Follow-up recommendations for transplant recipients have been published by the major North American and European transplant groups, the CDC, and the Infectious Diseases Society of America.[16,17]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for immune system late effects information including risk factors, evaluation, and health counseling.


  1. Immunization in special circumstances. In: Pickering LK, Baker CJ, Kimberlin DW, et al., eds.: Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, Ill: American Academy of Pediatrics, 2012, pp 69-109.
  2. Kaiser CW: Complications from staging laparotomy for Hodgkin disease. J Surg Oncol 16 (4): 319-25, 1981. [PUBMED Abstract]
  3. Jockovich M, Mendenhall NP, Sombeck MD, et al.: Long-term complications of laparotomy in Hodgkin's disease. Ann Surg 219 (6): 615-21; discussion 621-4, 1994. [PUBMED Abstract]
  4. Coleman CN, McDougall IR, Dailey MO, et al.: Functional hyposplenia after splenic irradiation for Hodgkin's disease. Ann Intern Med 96 (1): 44-7, 1982. [PUBMED Abstract]
  5. Weiner MA, Landmann RG, DeParedes L, et al.: Vesiculated erythrocytes as a determination of splenic reticuloendothelial function in pediatric patients with Hodgkin's disease. J Pediatr Hematol Oncol 17 (4): 338-41, 1995. [PUBMED Abstract]
  6. Centers for Disease Control and Prevention (CDC): 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 60 (40): 1391-2, 2011. [PUBMED Abstract]
  7. Pickering LK, Baker CJ, Kimberlin DW, et al., eds.: Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, Ill: American Academy of Pediatrics, 2012. Also available online. Last accessed December 17, 2014.
  8. Schwartz C L, Hobbie WL, Constine LS, et al., eds.: Survivors of Childhood Cancer: Assessment and Management. St. Louis, Mo: Mosby, 1994.
  9. Leung W, Neale G, Behm F, et al.: Deficient innate immunity, thymopoiesis, and gene expression response to radiation in survivors of childhood acute lymphoblastic leukemia. Cancer Epidemiol 34 (3): 303-8, 2010. [PUBMED Abstract]
  10. Aytac S, Yalcin SS, Cetin M, et al.: Measles, mumps, and rubella antibody status and response to immunization in children after therapy for acute lymphoblastic leukemia. Pediatr Hematol Oncol 27 (5): 333-43, 2010. [PUBMED Abstract]
  11. Brodtman DH, Rosenthal DW, Redner A, et al.: Immunodeficiency in children with acute lymphoblastic leukemia after completion of modern aggressive chemotherapeutic regimens. J Pediatr 146 (5): 654-61, 2005. [PUBMED Abstract]
  12. Ruggiero A, Battista A, Coccia P, et al.: How to manage vaccinations in children with cancer. Pediatr Blood Cancer 57 (7): 1104-8, 2011. [PUBMED Abstract]
  13. Patel SR, Chisholm JC, Heath PT: Vaccinations in children treated with standard-dose cancer therapy or hematopoietic stem cell transplantation. Pediatr Clin North Am 55 (1): 169-86, xi, 2008. [PUBMED Abstract]
  14. Olkinuora HA, Taskinen MH, Saarinen-Pihkala UM, et al.: Multiple viral infections post-hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts. Pediatr Transplant 14 (2): 242-8, 2010. [PUBMED Abstract]
  15. Inaba H, Hartford CM, Pei D, et al.: Longitudinal analysis of antibody response to immunization in paediatric survivors after allogeneic haematopoietic stem cell transplantation. Br J Haematol 156 (1): 109-17, 2012. [PUBMED Abstract]
  16. Rizzo JD, Wingard JR, Tichelli A, et al.: Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant 37 (3): 249-61, 2006. [PUBMED Abstract]
  17. Tomblyn M, Chiller T, Einsele H, et al.: Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 15 (10): 1143-238, 2009. [PUBMED Abstract]
  • Updated: April 21, 2015