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Immunisation strategies for children with cancer
Mini-symposium
Immunisation 1
Immunisation strategies for children with cancer
F. Cowie, S. T. Meller Children with malignancy are increasingly likely to survive their disease, and more than 60% of children with Acute Lymphoblastic Leukaemia (ALL) now have a five year disease free survival rate. The annual incidence of childhood cancer is such that 1200 new cases will be diagnosed annually in England and Wales, more than half of these children will survive and need to be reintegrated into the general medical service.
It is widely recognised that on a national scale immunisation needs to continue at or above the present level in order to maintain the decline in cases of measles, and to decrease the exposure of immunocompromised children. The basis for the concept of herd immunity requires that the national uptake of immunisations reaches a high level so that a small number of unimmunised children will be ‘safe’ from infection without being immunised. This will obviously only work if the vaccination uptake rate remains very high and the incidence of natural infection drops to virtually zero.
Benefit of immunisation programs The importance of immunisation programs is beyond doubt in the prevention of infectious disease and has resulted in a decline in the childhood death rate since the introduction of the diphtheria vaccine in 1940.’ Measles remains an important cause of morbidity and mortality and is associated with complications in 1 in 15 notified cases. The annual incidence of measles in the UK has fallen from 800000 per year, with a death rate of 1000 per year (prior to the introduction of vaccination in 1968), to an incidence of 9985 with no deaths reported in 1991. Measles vaccine uptake reached 92% in England in 1992. This is however no reason for complacency. In immunosupressed children measles is a serious infection, and the presentation is often atypical with no history of a contact. A high index of suspicion is needed to diagnose measles in the absence of either a contact or typical features. In these children the infection runs a more fulminant course; measles pneumonitis and delayed encephalitis (which is distinct from subacute sclerosing panencephalitis) are common and often fatal. Out of 18 cases of measles reported in 1043 children with ALL, there were 15 deaths and one child was left severely handicapped.’
Immunisation The object of immunisation is to raise the degree of resistance to specific infections by increasing the organism specific antibody level within an individual. Active immunity is raised by introducing an antigen to which the host develops humoral or cell mediated immunity, this is usually long lasting and often lifelong, though it may require boosting at intervals. Passive immunity is conferred by the injection of antibodies via an infusion of human immunoglobulin, these may be general or disease specific (i.e. tetanus, hepatitis B, rabies, varicella zoster or cytomegalovirus). Passive immunity however is only protective for a short period, and is often used to cover exposure to an infectious agent whilst active immunity is being induced. In individuals who have an acquired immune defect, previously acquired immunity may decline or disappear, and the induction of new active immunity may be difficult to achieve with suboptimal response to vaccination schedules. There is also a risk from the use of live virus vaccines, with reports of the vaccine virus strain causing significant clinical disease. Measles vaccine pneumonitis has been reported in
F. Cowie and S. T. Meller Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT Correspondence and requests for offprints to FC. Current Poediutrics (1993) 3, 192-196 0 1993 Longman Group UK Ltd
192
IMMUNISATION
immunocompromised patients months nation with earlier vaccines3
There are several groups of children and adults who have both decreased resistance to infections and who are at increased risk should they be infected owing to immune deficiency. Acquired immune deficiency may be due to infection (e.g. HIV), malnutrition, drugs (e.g. steroids and cytotoxics), radiation and malignant disease (especially leukaemia and lymphoma) . Children with malignant disease are at risk from infectious diseases for several reasons. They may have disease related immune suppression (i.e. abnormal cellular and humoral immunity), during treatment they will undergo periods of myelosuppression, they may have an indwelling central line, damaged gastrointestinal mucosa or alterations in their usual endogenous microflora. Most children with malignant disease will be treated with either chemotherapy or radiotherapy, both of which can result in impaired immune function which lasts for a variable length of time after the end of treatment. Both T and B lymphocyte function are impaired post chemotherapy, as measured by opsonic activity, bacterial lysis and neutralisation of bacterial toxins. Splenic irradiation (for instance during total body irradiation) or splenectomy (as in the staging of Hodgkin’s disease under some circumstances) can result in temporary or permanent loss of splenic function, The spleen is important as a mechanical filter for microorganisms, but it also improves opsonisation and has a role in the production of antibodies. Post splenectomy infection is commonly with encapsulated bacteria such as pneumococcus, haemophilus and meningococcus. The recovery of immune function after bone marrow transplantation (BMT) has been the subject of limited investigation. A study in 1981 indicated that the most important factors in the ability to respond to an antigenic challenge were the time elapsed since transplantation, presence of chronic graft-versus-host disease (GVHD) and antithymocyte globulin treatment after BMT.4 A more recent study ( 1993) has shown that pre transplant T cell depletion of the donor bone marrow did not significantly affect immune reconstitution, and that T cell numbers remained low until 12 months post transplant, whilst B cell numbers were normal by three months.5 They also observed that the principal effect of GVHD was to further depress the CD4 T cell population, and that in all cases immunoglobulin recovery was most rapid for IgM and IgA, with IgG recovery taking up to 1 year. However it has been demonstrated that patients are able to mount an antibody response to vaccination as early as 6 months after BMT.6
FOR CHILDREN
WITH CANCER
193
Generaladvice
after vacci-
Patients at special risk
STRATEGIES
In general we place very few restrictions on the activities of children who are undergoing, or who have recently finished treatment for malignancy. The exception being those children who have received a bone marrow transplant and who will have had near total ablation of their immune function. These children depend upon the recovery of function in the newly engrafted marrow in order to mount an immune response in the future. This means that they are both at increased risk from infection and that infection or intercurrent illnesses may delay the recovery of immune function. Providing they feel well enough our patients are allowed to attend school or nursery, to play with their friends and to go out to the park or cinema. It is recognised that they will be at increased risk of picking up common viral infections whilst lymphopenic. If this should occur and the child is not also neutropenic, conservative management is all that is required, such a viral infection is generally well tolerated and seldom severe. However in patients who are neutropenic intravenous broad spectrum antibiotics in hospital are mandatory should they develop a febrile illness, until bacterial infection has been excluded. Some consideration and advice needs to be given to the parents, school and nursery regarding the health and vaccination status of other children with whom the patient may come into direct contact. The Head Teacher and School Medical Officer are advised to send a letter to the parents of other children in the same class at school or nursery to encourage parents to ensure that their childs vaccinations are up to date, and also to inform the school of any cases (suspected or proven) of chicken pox or measles.
Specific schemesfor vaccination 1. Children with malignancy (not receiving a BMT) Completed primary immunisation before treatment for cancer (i.e. DTP, Hib, oral polio and MMR) l
No further vaccinations until 6 months after the end of treatment, then:
Boost with DT/OPV/MMR Boost with Pertussis if under 2 years old Boost with Hib if under 4 years old Check tuberculin test if previously had BCG, consider revaccination Give BCG at 13 years if not previously immunised Give rubella to girls at ( lo- 14 years) if not had MMR 2. Children with malignancy (not receiving BMT) Not completely immunised l
Continue with primary vaccination schedule as close to ‘on time’ as possible, but no live vaccines
194 CURRENT PAEDIATRICS
l
so use enhanced inactivated polio vaccine eIPV instead of OPV, and delay MMR until 6 months after the end of treatment. At 6 months after the end of treatment:
Give MMR Boost with DT and OPV Boost with Pertussis if under 2 years old Boost with Hib if under 4 years old Check antibody levels 4-8 weeks later Check Tuberculin test if previously had BCG, consider revaccination Give BCG at 13 years if not previously immunised 3. Children who have had a bone marrow transplant No vaccinations until 6 months after the end of all immunosupressive treatment when: Revaccinate with DT (i.e. three doses) Revaccinate with Pertussis if under 2 years old (i.e. three doses) Revaccinate with Hib if under 4 years old (i.e. three doses) l No live vaccines until 12 months after the end of immunosupressive treatment when: Give MMR and revaccinate with OPV (i.e. three doses) Check Tuberculin test if previously had BCG, consider revaccination Give BCG at 13 years if not previously immunised l
These patients include those who have had high dose chemotherapy with autologous marrow or stem cell transplant, allografts and matched unrelated donor transplants (MUDS). Following the pre transplant chemotherapy and in some cases total body irradiation (TBI) that these patients receive, they will have severely impaired immunity for several months. Allografted patients (including those receiving a MUD transplant) usually take cyclosporin for 6 months as graft versus host disease prevention, and so will be unable to receive live vaccinations until 18 months post transplant. In patients who have received an allograft or MUD transplant and who have problems with chronic graft versus host disease even further delay prior to vaccination may be advisable (due to the continuing immunosupression and the effect of GvHD), this needs to be considered on an individual basis. Some patients who have had a bone marrow transplant will have received TBI as part of their treatment. All patients who have had TBI are regarded as having radiation induced splenic dysfunction. This may be permanent and is an important cause of mortality with pneumococcal septicaemia causing fatalities several years after TBI and bone marrow transplantation.7 Such patients receive prophylactic oral penicillin V from the time of discharge from hospital. In patients who are unable
to tolerate penicillin, erythromycin or cotrimoxazole are acceptable alternatives. Amoxycilin may be more suitable for those children under the age of 5 years as it is more predictably absorbed, and also provides cover against haemophilus infection. The duration of such oral prophylaxis is unclear, we currently recommend that it be lifelong, or perhaps that it should continue until they have a demonstrated recovery in their immune function. Immunisations in later life Once more than 6 months have elapsed since immunosuppressive therapy any vaccination is safe and should be given if indicated, this includes vaccination for travel or work purposes (i.e. typhoid, hepatitis A or B). It is important that the BCG and rubella immunisations are given at school at the appropriate time if this is possible. Siblings and close relatives Unimmunised siblings should be fully immunised according to the national schedule. They can receive all live vaccinations except the oral polio vaccination. Oral polio vaccination is contraindicated in siblings or close household contacts due to the shedding of live polio virus in the stools post vaccination. This has caused clinical polio infection in immunosuppressed and normal people. The risk continues for up to 6 weeks, but is greatest from infants, any person requiring nappies, or from those with diarrhoea. If polio vaccination needs to be given to a sibling or household contact of a child on (or up to 6 months off) treatment, they should be given eIPV. In the UK primary polio vaccination is performed using three doses of live vaccine, this provides good mucosal and humoral immunity. If a course of eIPV is used for primary vaccination mucosal immunity will not develop, this is the usual situation in some countries (e.g. Sweden), and is not detrimental to the health of the population. Mixing the two preparations (eIPV and OPV) within a primary course of vaccination is acceptable if necessary. Smallpox vaccination is absolutely contraindicated in relatives and household contacts of children on or up to 6 months off immunosupressive therapy. Specific infectious diseases Chicken pox Chicken pox is a highly infectious disease and is widely prevalent in the community. Most children will be exposed to it at some stage, however previous exposure to chicken pox is no guarantee of lasting immunity. All the children treated at the Royal Marsden Hospital will have their varicella antibody titres evaluated prior to starting treatment for malignant disease (regardless of any history of
IMMUNISATION
chicken pox). A titre of above ten is considered partially protective in the event of contact with an infected individual and these patients are not routinely given Zoster Immune Globulin (ZIG) after a contact. Immunosuppressed children are at increased risk of severe or disseminated varicella infections, for this reason we encourage a greater awareness of chicken pox and shingles amongst our families and the schools and nurseries they attend. Contact with chicken pox warrants the administration of ZIG if the contact has been ‘significant’. A contact is considered to be significant if the infected child lives in the same house, was playing with or directly in contact with the child at risk. Merely being in the same class room or playground is not sufhcient. In the case of shingles, contact has to occur between exposed vesicles and the child at risk (virus is only shed from the vesicles). If a child has had a contact with chicken pox or shingles and they are being treated for leukaemia (this includes patients up to 6 months off treatment) they will be given ZIG if they had an insufficient varicella antibody titre at presentation. Children who have had sufficient antibodies at presentation, and all children being treated for non leukaemic malignancies do not receive ZIG in the event of a contact. However any child who has had a bone marrow transplant will be given ZIG in the event of a significant contact regardless of their pre treatment antibody levels, these children are considered at risk until 12 months from treatment for autografts, or 18 months for patients who have received an allograft or MUD. The rationale behind this policy is: It is uncertain how useful ZIG actually is in preventing post exposure disease in at risk individuals. ZIG is in relatively short supply. Children being treated for a non leukaemic condition will generally have a better functioning immune system. Children with leukaemia will probably retain some of any previously acquired immunity. However post transplant (for whatever condition) all previous immunity must be assumed to have been removed by the treatment. ZIG is only effective if given within 72 h of a contact, and should theoretically remain effective for a few weeks. In the event of a significant contact in a child who would be given ZIG but has a contact history of greater than 72 h, a 2-week course of oral acyclovir should be given to prevent or ameliorate the development of overt infection. Whether or not ZIG or prophylactic acyclovir has been given any child on or up to 6 months post immunosuppressive treatment (i.e. 12 months for an autograft, 18 months for an allograft or MUD), who develops chicken pox or shingles needs to be treated with high dose
STRATEGIES
FOR CHILDREN
WITH CANCER
195
acyclovir. This is started as soon as possible after the appearance of vesicles, and is given intravenously until no new crops of vesicles have appeared, the child is systemically well and afebrile. We then continue with oral acyclovir to complete a lo-day course, or to continue until all the lesions have crusted over if this is longer. Children on chemotherapy for leukaemia should continue to take their medication unless neutropenia develops, however steroids should be avoided until all the lesions have crusted. Measles
Measles remains a devastating infection in immunosupressed individuals with an extremely high mortality rate. Overt measles infection in an immunocompromised patient is usually atypical in presentation, and the diagnosis relies upon clinical acumen and a good rapid viral diagnostic service. In a series of 401 children with (any) malignancy there were 17 cases of measles, none of these had either been vaccinated or had had natural measles infection.* Measles vaccine has been shown to provide both effective and long lasting protection in immune competent people, it is therefore essential that the uptake of this vaccination be maintained at as high a level as possible. There is no effective treatment for established measles infection, the main therapeutic drive is towards preventing secondary infections occurring in immunosuppressed patients with measles. Any child who has a proper measles contact (as for chicken pox) will be treated with Human Normal Immune Globulin (HNIG), if they present within 72 h of a contact. If such a child subsequently develops measles infection they should be given immunoglobulin or hyperimmune measles IgG if available. They do not need to be hospitalised though they should stop any continuing chemotherapy, and be closely monitored for intercurrent infection. Measles infection under these circumstances will not produce a lasting measles immunity. Cytomegalovirus (CMV)
Infection with this ubiquitous herpes virus results in an 80% seroconversion rate by adulthood, and virus can be detected in the urine of up to 20% of asymptomatic children. Primary infection can result in a severe illness in immunocompromised people as can reactivation of a previously acquired infection. There is currently no vaccine available. However, avoidance of primary CMV infection is attempted in immunosupressed patients by ensuring that a CMV antibody negative patient does not receive CMV positive blood or blood products. High dose intravenous acyclovir is used to prevent CMV reactivation in CMV antibody positive patients undergoing a
I96
CURRENT
PAEDIATRICS
bone marrow transplantation (this also includes CMV negative recipients of CMV positive bone marrow). Overt CMV infection is treated with ganciclovir and immunoglobulin. The titre of CMV antibodies in the infused immunoglobulin appears to be less important than an immunomodulatory effect from serum proteins present in both standard and hyperimmune globulin.
Tuberculosis is a serious disseminated infection in immunocompromised patients. As the BCG vaccination is given at the age of 13 in the UK (except in certain high risk groups who are vaccinated at birth) many children with malignant disease will be susceptible to infection. Vaccination with BCG is contraindicated until at least 6 months from the end of immunosuppressive treatment as for other live vaccines. Nevertheless every attempt should be made to vaccinate these children in accordance with the national schedule given the above constraints. In theory children who have already had a BCG vaccination prior to treatment for cancer should be reassessed at an appropriate time following completion of treatment for malignant disease with a tuberculin skin test, and should proceed with a repeat BCG vaccination if it is negative.
This method of assessing vaccine uptake is not currently in routine use. The use of live vaccines in immunosupressed people has until recently been considered absolutely contraindicated, however the development of a live varicella vaccine in 1974 has been followed by investigation into its use in normal and immunocompromised children. This vaccination has been shown to be safe and effective in both these groups and protection lasts for at least three years in children with Leukaemia.’ The varicella vaccine is currently in use in Japan, France and the USA, and is available (on a named patient basis only) in the UK. The live varicella vaccine virus is not transmissible, however vaccination is associated with a risk of a macular papulovesicular rash or febrile illness in up to 40% of children on continuing chemotherapy for Leukaemia. Subsequent herpes zoster (due to vaccine virus strain) has been a concern, though it occurs less frequently (2.4% in patients with leukaemia) than herpes zoster due to wild type varicella infection.” The current recommendation is that this vaccination should not be given to severely immunocompromised (lymphopenic) children, however it should be possible to safely institute a policy of vaccination for those children who are varicella antibody negative on continuing chemotherapy for leukaemia, or prior to a bone marrow transplantation procedure.
Future prospects
References
It is rarely practical to delay the initiation of chemotherapy in a patient with malignant disease for 2-4 weeks whilst a child is immunised as has been suggested by some groups. However a case could be made for giving inactivated vaccines such as Hib, Pneumovax@, or hepatitis B vaccine to certain groups of children (i.e. Leukaemics on continuing chemotherapy). We are currently investigating a policy of giving patients who have had total body irradiation Pneumovax@ 1 year after bone marrow transplant and then measuring antibody titres. If they are able to mount an immune response to the vaccination it can be assumed that they are sufficiently immune competent to be able to cope with a natural antigenic challenge, and that they will be able to safely stop pneumococcal prophylaxis. If they are unable to mount an antibody response, the procedure needs to be repeated at a later date, and prophylaxis must be continued. The place of measuring serum antibody levels following vaccination remains unclear. In theory it is a useful and attractive way of monitoring the immune response to vaccination. The antibody level necessary for protection has not yet been adequately established, though the use of paired sera (before and after vaccination) may provide valuable information.
1. Immunisation against infectious diseases, HMSO publication; 1992. 2. Gray M, Hams I, Glass S, Eden 0, Morris Jones P, Stevens R. Mortality and morbidity caused by measles in children with malignant disease attending four major treatment centres: a retrospective review. B M J 1987; 295: 19-24. 3. Mitus A, Holloway A, Evans A et al. Attenuated measles vaccine in children with acute leukaemia. Am J Dis Child 1962; 103: 211. 4. Witherspoon R, Storb R, Ochs H et al. Recovery of antibody production in human allogeneic marrow graft recipients: Influence of time post transplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment. Blood 1981; 58: 360-368. 5. Foot A, Potter M, Donaldson C et al. Immune reconstitution after BMT in children. Bone Marrow Transplantation 1993; 11: 7-13. 6. Engelhard D, Nagler A, Hardan I et al. Antibody response to a two-dose regimen of influenza vaccine in allogeneic T celldepleted and autologous BMT recipients. Bone Marrow Transplantation 1993; 11: l-5. I. Winston D, Schiffman G, Wang D et al. Pneumococcal infections after human bone marrow transplantation. Ann Intern Med 1979; 91: 835-841. 8. Kemahan J. McOuillin J. Craft AW. Measles in children who have malignant d&ease. B M J 1987; 295: 15-I 8. 9. Gershon A, Steinberg S, and the Varicella Vaccine Collaborative Study Group of the National Institute of Allergy and Infectious Diseases. Persistence of immunity to varicella in children with leukaemia immunized with live attenuated varicella vaccine. N Engl J Med 1989; 320: 892-897. 10. Hardy I, Gershon A, Steinberg S et al. The incidence of zoster after immunization with live attenuated varicella vaccine: A study in children with leukemia. The New England Journal of Medicine 1991; 325: 1545-1550.
Tuberculosis
Immunisation 1
Immunisation strategies for children with cancer
F. Cowie, S. T. Meller Children with malignancy are increasingly likely to survive their disease, and more than 60% of children with Acute Lymphoblastic Leukaemia (ALL) now have a five year disease free survival rate. The annual incidence of childhood cancer is such that 1200 new cases will be diagnosed annually in England and Wales, more than half of these children will survive and need to be reintegrated into the general medical service.
It is widely recognised that on a national scale immunisation needs to continue at or above the present level in order to maintain the decline in cases of measles, and to decrease the exposure of immunocompromised children. The basis for the concept of herd immunity requires that the national uptake of immunisations reaches a high level so that a small number of unimmunised children will be ‘safe’ from infection without being immunised. This will obviously only work if the vaccination uptake rate remains very high and the incidence of natural infection drops to virtually zero.
Benefit of immunisation programs The importance of immunisation programs is beyond doubt in the prevention of infectious disease and has resulted in a decline in the childhood death rate since the introduction of the diphtheria vaccine in 1940.’ Measles remains an important cause of morbidity and mortality and is associated with complications in 1 in 15 notified cases. The annual incidence of measles in the UK has fallen from 800000 per year, with a death rate of 1000 per year (prior to the introduction of vaccination in 1968), to an incidence of 9985 with no deaths reported in 1991. Measles vaccine uptake reached 92% in England in 1992. This is however no reason for complacency. In immunosupressed children measles is a serious infection, and the presentation is often atypical with no history of a contact. A high index of suspicion is needed to diagnose measles in the absence of either a contact or typical features. In these children the infection runs a more fulminant course; measles pneumonitis and delayed encephalitis (which is distinct from subacute sclerosing panencephalitis) are common and often fatal. Out of 18 cases of measles reported in 1043 children with ALL, there were 15 deaths and one child was left severely handicapped.’
Immunisation The object of immunisation is to raise the degree of resistance to specific infections by increasing the organism specific antibody level within an individual. Active immunity is raised by introducing an antigen to which the host develops humoral or cell mediated immunity, this is usually long lasting and often lifelong, though it may require boosting at intervals. Passive immunity is conferred by the injection of antibodies via an infusion of human immunoglobulin, these may be general or disease specific (i.e. tetanus, hepatitis B, rabies, varicella zoster or cytomegalovirus). Passive immunity however is only protective for a short period, and is often used to cover exposure to an infectious agent whilst active immunity is being induced. In individuals who have an acquired immune defect, previously acquired immunity may decline or disappear, and the induction of new active immunity may be difficult to achieve with suboptimal response to vaccination schedules. There is also a risk from the use of live virus vaccines, with reports of the vaccine virus strain causing significant clinical disease. Measles vaccine pneumonitis has been reported in
F. Cowie and S. T. Meller Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT Correspondence and requests for offprints to FC. Current Poediutrics (1993) 3, 192-196 0 1993 Longman Group UK Ltd
192
IMMUNISATION
immunocompromised patients months nation with earlier vaccines3
There are several groups of children and adults who have both decreased resistance to infections and who are at increased risk should they be infected owing to immune deficiency. Acquired immune deficiency may be due to infection (e.g. HIV), malnutrition, drugs (e.g. steroids and cytotoxics), radiation and malignant disease (especially leukaemia and lymphoma) . Children with malignant disease are at risk from infectious diseases for several reasons. They may have disease related immune suppression (i.e. abnormal cellular and humoral immunity), during treatment they will undergo periods of myelosuppression, they may have an indwelling central line, damaged gastrointestinal mucosa or alterations in their usual endogenous microflora. Most children with malignant disease will be treated with either chemotherapy or radiotherapy, both of which can result in impaired immune function which lasts for a variable length of time after the end of treatment. Both T and B lymphocyte function are impaired post chemotherapy, as measured by opsonic activity, bacterial lysis and neutralisation of bacterial toxins. Splenic irradiation (for instance during total body irradiation) or splenectomy (as in the staging of Hodgkin’s disease under some circumstances) can result in temporary or permanent loss of splenic function, The spleen is important as a mechanical filter for microorganisms, but it also improves opsonisation and has a role in the production of antibodies. Post splenectomy infection is commonly with encapsulated bacteria such as pneumococcus, haemophilus and meningococcus. The recovery of immune function after bone marrow transplantation (BMT) has been the subject of limited investigation. A study in 1981 indicated that the most important factors in the ability to respond to an antigenic challenge were the time elapsed since transplantation, presence of chronic graft-versus-host disease (GVHD) and antithymocyte globulin treatment after BMT.4 A more recent study ( 1993) has shown that pre transplant T cell depletion of the donor bone marrow did not significantly affect immune reconstitution, and that T cell numbers remained low until 12 months post transplant, whilst B cell numbers were normal by three months.5 They also observed that the principal effect of GVHD was to further depress the CD4 T cell population, and that in all cases immunoglobulin recovery was most rapid for IgM and IgA, with IgG recovery taking up to 1 year. However it has been demonstrated that patients are able to mount an antibody response to vaccination as early as 6 months after BMT.6
FOR CHILDREN
WITH CANCER
193
Generaladvice
after vacci-
Patients at special risk
STRATEGIES
In general we place very few restrictions on the activities of children who are undergoing, or who have recently finished treatment for malignancy. The exception being those children who have received a bone marrow transplant and who will have had near total ablation of their immune function. These children depend upon the recovery of function in the newly engrafted marrow in order to mount an immune response in the future. This means that they are both at increased risk from infection and that infection or intercurrent illnesses may delay the recovery of immune function. Providing they feel well enough our patients are allowed to attend school or nursery, to play with their friends and to go out to the park or cinema. It is recognised that they will be at increased risk of picking up common viral infections whilst lymphopenic. If this should occur and the child is not also neutropenic, conservative management is all that is required, such a viral infection is generally well tolerated and seldom severe. However in patients who are neutropenic intravenous broad spectrum antibiotics in hospital are mandatory should they develop a febrile illness, until bacterial infection has been excluded. Some consideration and advice needs to be given to the parents, school and nursery regarding the health and vaccination status of other children with whom the patient may come into direct contact. The Head Teacher and School Medical Officer are advised to send a letter to the parents of other children in the same class at school or nursery to encourage parents to ensure that their childs vaccinations are up to date, and also to inform the school of any cases (suspected or proven) of chicken pox or measles.
Specific schemesfor vaccination 1. Children with malignancy (not receiving a BMT) Completed primary immunisation before treatment for cancer (i.e. DTP, Hib, oral polio and MMR) l
No further vaccinations until 6 months after the end of treatment, then:
Boost with DT/OPV/MMR Boost with Pertussis if under 2 years old Boost with Hib if under 4 years old Check tuberculin test if previously had BCG, consider revaccination Give BCG at 13 years if not previously immunised Give rubella to girls at ( lo- 14 years) if not had MMR 2. Children with malignancy (not receiving BMT) Not completely immunised l
Continue with primary vaccination schedule as close to ‘on time’ as possible, but no live vaccines
194 CURRENT PAEDIATRICS
l
so use enhanced inactivated polio vaccine eIPV instead of OPV, and delay MMR until 6 months after the end of treatment. At 6 months after the end of treatment:
Give MMR Boost with DT and OPV Boost with Pertussis if under 2 years old Boost with Hib if under 4 years old Check antibody levels 4-8 weeks later Check Tuberculin test if previously had BCG, consider revaccination Give BCG at 13 years if not previously immunised 3. Children who have had a bone marrow transplant No vaccinations until 6 months after the end of all immunosupressive treatment when: Revaccinate with DT (i.e. three doses) Revaccinate with Pertussis if under 2 years old (i.e. three doses) Revaccinate with Hib if under 4 years old (i.e. three doses) l No live vaccines until 12 months after the end of immunosupressive treatment when: Give MMR and revaccinate with OPV (i.e. three doses) Check Tuberculin test if previously had BCG, consider revaccination Give BCG at 13 years if not previously immunised l
These patients include those who have had high dose chemotherapy with autologous marrow or stem cell transplant, allografts and matched unrelated donor transplants (MUDS). Following the pre transplant chemotherapy and in some cases total body irradiation (TBI) that these patients receive, they will have severely impaired immunity for several months. Allografted patients (including those receiving a MUD transplant) usually take cyclosporin for 6 months as graft versus host disease prevention, and so will be unable to receive live vaccinations until 18 months post transplant. In patients who have received an allograft or MUD transplant and who have problems with chronic graft versus host disease even further delay prior to vaccination may be advisable (due to the continuing immunosupression and the effect of GvHD), this needs to be considered on an individual basis. Some patients who have had a bone marrow transplant will have received TBI as part of their treatment. All patients who have had TBI are regarded as having radiation induced splenic dysfunction. This may be permanent and is an important cause of mortality with pneumococcal septicaemia causing fatalities several years after TBI and bone marrow transplantation.7 Such patients receive prophylactic oral penicillin V from the time of discharge from hospital. In patients who are unable
to tolerate penicillin, erythromycin or cotrimoxazole are acceptable alternatives. Amoxycilin may be more suitable for those children under the age of 5 years as it is more predictably absorbed, and also provides cover against haemophilus infection. The duration of such oral prophylaxis is unclear, we currently recommend that it be lifelong, or perhaps that it should continue until they have a demonstrated recovery in their immune function. Immunisations in later life Once more than 6 months have elapsed since immunosuppressive therapy any vaccination is safe and should be given if indicated, this includes vaccination for travel or work purposes (i.e. typhoid, hepatitis A or B). It is important that the BCG and rubella immunisations are given at school at the appropriate time if this is possible. Siblings and close relatives Unimmunised siblings should be fully immunised according to the national schedule. They can receive all live vaccinations except the oral polio vaccination. Oral polio vaccination is contraindicated in siblings or close household contacts due to the shedding of live polio virus in the stools post vaccination. This has caused clinical polio infection in immunosuppressed and normal people. The risk continues for up to 6 weeks, but is greatest from infants, any person requiring nappies, or from those with diarrhoea. If polio vaccination needs to be given to a sibling or household contact of a child on (or up to 6 months off) treatment, they should be given eIPV. In the UK primary polio vaccination is performed using three doses of live vaccine, this provides good mucosal and humoral immunity. If a course of eIPV is used for primary vaccination mucosal immunity will not develop, this is the usual situation in some countries (e.g. Sweden), and is not detrimental to the health of the population. Mixing the two preparations (eIPV and OPV) within a primary course of vaccination is acceptable if necessary. Smallpox vaccination is absolutely contraindicated in relatives and household contacts of children on or up to 6 months off immunosupressive therapy. Specific infectious diseases Chicken pox Chicken pox is a highly infectious disease and is widely prevalent in the community. Most children will be exposed to it at some stage, however previous exposure to chicken pox is no guarantee of lasting immunity. All the children treated at the Royal Marsden Hospital will have their varicella antibody titres evaluated prior to starting treatment for malignant disease (regardless of any history of
IMMUNISATION
chicken pox). A titre of above ten is considered partially protective in the event of contact with an infected individual and these patients are not routinely given Zoster Immune Globulin (ZIG) after a contact. Immunosuppressed children are at increased risk of severe or disseminated varicella infections, for this reason we encourage a greater awareness of chicken pox and shingles amongst our families and the schools and nurseries they attend. Contact with chicken pox warrants the administration of ZIG if the contact has been ‘significant’. A contact is considered to be significant if the infected child lives in the same house, was playing with or directly in contact with the child at risk. Merely being in the same class room or playground is not sufhcient. In the case of shingles, contact has to occur between exposed vesicles and the child at risk (virus is only shed from the vesicles). If a child has had a contact with chicken pox or shingles and they are being treated for leukaemia (this includes patients up to 6 months off treatment) they will be given ZIG if they had an insufficient varicella antibody titre at presentation. Children who have had sufficient antibodies at presentation, and all children being treated for non leukaemic malignancies do not receive ZIG in the event of a contact. However any child who has had a bone marrow transplant will be given ZIG in the event of a significant contact regardless of their pre treatment antibody levels, these children are considered at risk until 12 months from treatment for autografts, or 18 months for patients who have received an allograft or MUD. The rationale behind this policy is: It is uncertain how useful ZIG actually is in preventing post exposure disease in at risk individuals. ZIG is in relatively short supply. Children being treated for a non leukaemic condition will generally have a better functioning immune system. Children with leukaemia will probably retain some of any previously acquired immunity. However post transplant (for whatever condition) all previous immunity must be assumed to have been removed by the treatment. ZIG is only effective if given within 72 h of a contact, and should theoretically remain effective for a few weeks. In the event of a significant contact in a child who would be given ZIG but has a contact history of greater than 72 h, a 2-week course of oral acyclovir should be given to prevent or ameliorate the development of overt infection. Whether or not ZIG or prophylactic acyclovir has been given any child on or up to 6 months post immunosuppressive treatment (i.e. 12 months for an autograft, 18 months for an allograft or MUD), who develops chicken pox or shingles needs to be treated with high dose
STRATEGIES
FOR CHILDREN
WITH CANCER
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acyclovir. This is started as soon as possible after the appearance of vesicles, and is given intravenously until no new crops of vesicles have appeared, the child is systemically well and afebrile. We then continue with oral acyclovir to complete a lo-day course, or to continue until all the lesions have crusted over if this is longer. Children on chemotherapy for leukaemia should continue to take their medication unless neutropenia develops, however steroids should be avoided until all the lesions have crusted. Measles
Measles remains a devastating infection in immunosupressed individuals with an extremely high mortality rate. Overt measles infection in an immunocompromised patient is usually atypical in presentation, and the diagnosis relies upon clinical acumen and a good rapid viral diagnostic service. In a series of 401 children with (any) malignancy there were 17 cases of measles, none of these had either been vaccinated or had had natural measles infection.* Measles vaccine has been shown to provide both effective and long lasting protection in immune competent people, it is therefore essential that the uptake of this vaccination be maintained at as high a level as possible. There is no effective treatment for established measles infection, the main therapeutic drive is towards preventing secondary infections occurring in immunosuppressed patients with measles. Any child who has a proper measles contact (as for chicken pox) will be treated with Human Normal Immune Globulin (HNIG), if they present within 72 h of a contact. If such a child subsequently develops measles infection they should be given immunoglobulin or hyperimmune measles IgG if available. They do not need to be hospitalised though they should stop any continuing chemotherapy, and be closely monitored for intercurrent infection. Measles infection under these circumstances will not produce a lasting measles immunity. Cytomegalovirus (CMV)
Infection with this ubiquitous herpes virus results in an 80% seroconversion rate by adulthood, and virus can be detected in the urine of up to 20% of asymptomatic children. Primary infection can result in a severe illness in immunocompromised people as can reactivation of a previously acquired infection. There is currently no vaccine available. However, avoidance of primary CMV infection is attempted in immunosupressed patients by ensuring that a CMV antibody negative patient does not receive CMV positive blood or blood products. High dose intravenous acyclovir is used to prevent CMV reactivation in CMV antibody positive patients undergoing a
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CURRENT
PAEDIATRICS
bone marrow transplantation (this also includes CMV negative recipients of CMV positive bone marrow). Overt CMV infection is treated with ganciclovir and immunoglobulin. The titre of CMV antibodies in the infused immunoglobulin appears to be less important than an immunomodulatory effect from serum proteins present in both standard and hyperimmune globulin.
Tuberculosis is a serious disseminated infection in immunocompromised patients. As the BCG vaccination is given at the age of 13 in the UK (except in certain high risk groups who are vaccinated at birth) many children with malignant disease will be susceptible to infection. Vaccination with BCG is contraindicated until at least 6 months from the end of immunosuppressive treatment as for other live vaccines. Nevertheless every attempt should be made to vaccinate these children in accordance with the national schedule given the above constraints. In theory children who have already had a BCG vaccination prior to treatment for cancer should be reassessed at an appropriate time following completion of treatment for malignant disease with a tuberculin skin test, and should proceed with a repeat BCG vaccination if it is negative.
This method of assessing vaccine uptake is not currently in routine use. The use of live vaccines in immunosupressed people has until recently been considered absolutely contraindicated, however the development of a live varicella vaccine in 1974 has been followed by investigation into its use in normal and immunocompromised children. This vaccination has been shown to be safe and effective in both these groups and protection lasts for at least three years in children with Leukaemia.’ The varicella vaccine is currently in use in Japan, France and the USA, and is available (on a named patient basis only) in the UK. The live varicella vaccine virus is not transmissible, however vaccination is associated with a risk of a macular papulovesicular rash or febrile illness in up to 40% of children on continuing chemotherapy for Leukaemia. Subsequent herpes zoster (due to vaccine virus strain) has been a concern, though it occurs less frequently (2.4% in patients with leukaemia) than herpes zoster due to wild type varicella infection.” The current recommendation is that this vaccination should not be given to severely immunocompromised (lymphopenic) children, however it should be possible to safely institute a policy of vaccination for those children who are varicella antibody negative on continuing chemotherapy for leukaemia, or prior to a bone marrow transplantation procedure.
Future prospects
References
It is rarely practical to delay the initiation of chemotherapy in a patient with malignant disease for 2-4 weeks whilst a child is immunised as has been suggested by some groups. However a case could be made for giving inactivated vaccines such as Hib, Pneumovax@, or hepatitis B vaccine to certain groups of children (i.e. Leukaemics on continuing chemotherapy). We are currently investigating a policy of giving patients who have had total body irradiation Pneumovax@ 1 year after bone marrow transplant and then measuring antibody titres. If they are able to mount an immune response to the vaccination it can be assumed that they are sufficiently immune competent to be able to cope with a natural antigenic challenge, and that they will be able to safely stop pneumococcal prophylaxis. If they are unable to mount an antibody response, the procedure needs to be repeated at a later date, and prophylaxis must be continued. The place of measuring serum antibody levels following vaccination remains unclear. In theory it is a useful and attractive way of monitoring the immune response to vaccination. The antibody level necessary for protection has not yet been adequately established, though the use of paired sera (before and after vaccination) may provide valuable information.
1. Immunisation against infectious diseases, HMSO publication; 1992. 2. Gray M, Hams I, Glass S, Eden 0, Morris Jones P, Stevens R. Mortality and morbidity caused by measles in children with malignant disease attending four major treatment centres: a retrospective review. B M J 1987; 295: 19-24. 3. Mitus A, Holloway A, Evans A et al. Attenuated measles vaccine in children with acute leukaemia. Am J Dis Child 1962; 103: 211. 4. Witherspoon R, Storb R, Ochs H et al. Recovery of antibody production in human allogeneic marrow graft recipients: Influence of time post transplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment. Blood 1981; 58: 360-368. 5. Foot A, Potter M, Donaldson C et al. Immune reconstitution after BMT in children. Bone Marrow Transplantation 1993; 11: 7-13. 6. Engelhard D, Nagler A, Hardan I et al. Antibody response to a two-dose regimen of influenza vaccine in allogeneic T celldepleted and autologous BMT recipients. Bone Marrow Transplantation 1993; 11: l-5. I. Winston D, Schiffman G, Wang D et al. Pneumococcal infections after human bone marrow transplantation. Ann Intern Med 1979; 91: 835-841. 8. Kemahan J. McOuillin J. Craft AW. Measles in children who have malignant d&ease. B M J 1987; 295: 15-I 8. 9. Gershon A, Steinberg S, and the Varicella Vaccine Collaborative Study Group of the National Institute of Allergy and Infectious Diseases. Persistence of immunity to varicella in children with leukaemia immunized with live attenuated varicella vaccine. N Engl J Med 1989; 320: 892-897. 10. Hardy I, Gershon A, Steinberg S et al. The incidence of zoster after immunization with live attenuated varicella vaccine: A study in children with leukemia. The New England Journal of Medicine 1991; 325: 1545-1550.
Tuberculosis