That said, the recommendations therein have been mostly adapted from the latest recommendations of the Infectious Disease Society of America (IDSA) clinical practice guidelines on immunization of immuno-compromised hosts published in 2013 [4], which understandably does not cover all the issues relevant to infectious diseases (and immunization practices) in Indian children. Moreover, the IDSA guidelines are not in agreement with the recommendations made by majority of similar other bodies worldwide. For example, it recommends re-immunization of children from 3 months following the end of their cancer chemotherapy, whereas most authorities would recommend a gap of 6 months from end of treatment for long lasting and effective immunity [5-10]. Furthermore, the recommendations in the IAP guidebook (2013-14) do not cover all vaccines, including some vaccines of local importance in India, neither does it provide guidance on the number of doses of each vaccine to be given in these children depending on their immunization status. The recommendations on immunization of contacts (siblings etc.) of these children are also missing.

Therefore, there remains an unmet need for a national consensus guideline addressing immunization related issues in children with cancer and their contacts/siblings which are in line with evidence-based consensus guidelines from around the world.

A Pubmed and Google search was undertaken to obtain all publications on immunization of children with cancer, all the relevant literature published on related topics were reviewed including national guidelines from the Infectious Disease Society of America [4], the Royal College of Paediatrics and Child Health, United Kingdom [5] as well as various institute/group specific guidelines published from the UK [6,7], Italy [8], Canada [9], Australia [10] and some of the developing countries like South Africa (personal communication Alan Davidson, University of Cape Town, South Africa) and Pakistan [11].

To review the current evidence and generate a nationally relevant guideline for immunization of children who receive chemotherapy for cancer. This guideline aims to ensure uniformity and streamline the current practice of immunising children with cancer during and after chemotherapy.

This guideline applies to children with cancer who have received chemotherapy. They do not apply to those who have received myeloablative chemotherapy e.g. those undergoing stem cell transplant (autologous or allogenic). They may also not be relevant to those children who only receive surgery and/or local radiotherapy for their cancer treatment e.g. low grade gliomas. This guideline does not cater to the needs of children treated with targeted therapy including monoclonal antibodies, small molecule targeted agents and other modalities of immunotherapy that are currently being increasingly used in the management of childhood cancers. We wish to include recommendations for the above group in the next revision of this guideline, anticipating availability of more evidence by then. This guideline does not take into account every possible scenario and the pediatrician/physician/oncologist immunizing these children has to ultimately decide what is most appropriate for a given situation. Factors guiding immunization of children with cancer during and after treatment include – immunization status prior to starting cancer treatment, current immunization schedule e.g. IAP or UIP (Universal Immunization Programme), risk of getting exposed to vaccine-preventable disease during treatment e.g. hepatitis B.

The current guideline would need updating in 2 years from the date of publishing and would need interim amendments in line with change in IAP-ACVIP recommendations on vaccines.

Pediatric cancers present with varying degrees of immune suppression [13,14]. This may range from minimal involvement of the immune system in children with localised solid malignancies to extensive immune suppression due to pancytopenia at presentation in acute leukemia. Some diseases present with specific immune involvement e.g., Hodgkin lymphoma and Burkitts lymphoma are associated with lack of lymphocytic response to various antigens [15] and variable levels of lymphocyte depletion, respectively [16]. Despite these changes, children rarely have clinically significant immune suppression prior to initiation of cytotoxic chemotherapy [14]. The degree of immune suppression depends on the intensity, duration and nature of chemotherapeutic agents [17]. Both cellular and humoral immunity is affected due to involvement of the T-cell/Natural killer (NK) cells and B-lymphocytes respectively [18]. The time to recovery seems to be longer for the T-cells as compared to the B-cells [18,19] and some of the immune defects may persist even longer after stoppage of chemotherapy [20]. Therefore, vaccine uptake during chemotherapy and for sometime thereafter may be erratic. Acquired immunity through previous infections or immunization also wanes due to effect of chemotherapy on immune system and needs boosting on recovery of immunity following end of chemotherapy [17]. Despite lack of consensus, most authorities recommend commencement of immunization at 6 months from the end of standard dose chemotherapy with the assumption that reasonable immunity is gained around that time [3-11].

Diptheria, Pertussis and Tetanus (DPT) vaccine [3,5]: Only DPT with whole cell pertussis component is included in UIP. TdaP and Td are not included. IAP recommended upper age limit for vaccination is 7 years. It is recommended 6 months after stoppage of chemotherapy and not during ongoing chemotherapy. The schedule comprises of three doses at 0,1 and 6 months (DwPT or DaPT if <7 years of age; TdaP 1st dose followed by given as Td 2nd and 3rd dose if > 7 years of age; TdaP only to be used beyond 7 years of age) in previously unimmunized children and a single booster dose (DwPT or DaPT if <7 years of age; TdaP if > 7 years of age) in those with previously completed immunization.

Injectable Polio Virus (IPV) vaccine [21,22]: Included in UIP as a four dose schedule. IAP recommended upper age limit for vaccination as 5 years. It is recommended 6 months after stoppage of chemotherapy and not during ongoing chemotherapy. The schedule for previously unimmunized children is two doses of IPV 2 months apart and 3rd dose after 6 months after 2nd dose whereas in previously immunised children a single booster dose of IPV is sufficient. In children with previously completed immunization with OPV, 2 doses of IPV one month apart is recommended. IPV is the preferred vaccine in these children. Fractional IPV [fIPV] can also be used for the initial 2 doses. OPV has to be given if IPV is not accessible.

TABLE I  Recommendations for Live Vaccines

Hepatitis B Vaccine (HBV): [23,24] : It is included in UIP. There is no IAP recommended upper age limit for vaccination.There is no need for further doses for children who have completed primary immunization schedule prior to diagnosis of cancer. In the current era, with improved safety of blood products [nucleic acid amplification (NAT) testing] as well as increasing hepatitis B immunization, active and passive immunization for hepatitis B is generally not recommended during treatment. If, however, there is risk of suboptimal blood transfusion practices in a child diagnosed with cancer who is unimmunized and who is hepatitis B surface antigen negative, then it is recommended to administer 4 doses of vaccine at 0, 1, 2 and 12 months at double dosage as well as age appropriate dose of hepatitis B immunoglobulin every 3 months till there is no risk of exposure to blood products. HBV vaccine is recommended 6 months after stoppage of chemotherapy as 3 doses at 0, 1 and 6 months in previously unimmunized children and a single booster dose in children with previously completed immunization.

TABLE II Recommendations for Non-live Vaccines

Hemophilus influenzae Type B Conjugate vaccine (HiB) [25]: Hib vaccine is included in UIP in some states. IAP has recommended upper age limit for vaccination as 5 years. It is not recommended during ongoing chemo-therapy. It is recommended 6 months after stoppage of chemotherapy as a single booster dose in children with previously completed immunization. In previously unimmunized children the schedule is age dependent (age 6-12 months - two doses 8 week apart, followed by booster at 12 months; age 12-15 months - one dose and booster at 18 months; age 15-60 months - one dose).

Pneumococcal vaccine [25]: Pneumococcal vaccines are not included in UIP. Pneumococcal conjugate vaccine (PCV) is recommended for routine use by IAP. Pneumococcal polysaccharide vaccine (PPSV) is only recommended for high-risk population. IAP recommen-ded upper age limit for vaccination as 5 years. Pneumococcal vaccines are not recommended during chemotherapy. Recommended schedule at 6 months after stoppage of chemotherapy is age dependent for previously unimmunized children (age <1 yr: 2 doses of PCV at 4-8 week interval followed by a booster dose between 12-15 months age; age 1-2 years: 2 doses of PCV 8 weeks apart; age 2-5 yrs: single dose of PCV). In children with previously completed immunization single booster dose of PCV is recommended. PPSV is not recommended in children with cancer undergoing standard dose chemotherapy.

Inactivated Hepatitis A vaccine [5,26]: Hepatitis A vaccines are not included in UIP. There is no IAP recommended upper age limit for vaccination. It is recommended 6 months after stoppage of chemotherapy and not during ongoing chemotherapy. Recommended schedule in previously unimmunized children comprises of two doses 6 months apart. In children with previously completed immunization, single booster dose is adequate.

Typhoid vaccine [11,25]: It is not included in UIP. There is no IAP recommended upper age limit for vaccination. It is recommended 6 months after stoppage of chemotherapy and not during ongoing chemotherapy. The recommended schedule includes a single dose of typhoid conjugate vaccine for both previously immunised as well as unimmunized children. No booster doses are recommended as of now.

Human Papilloma Virus Vaccine [3, 27]: It is not included in UIP. IAP recommended upper age limit for vaccination is 45 years. It is recommended 6 months after stoppage of chemotherapy and not during ongoing chemotherapy. The schedule in previously unimmunized girls are age dependent [age 9-14 years - two doses 6 months apart in females, age > 14 years – three doses at 0,1 and 6 months (bivalent HPV), or 0, 2 and 6 months quadrivalent (HPV) in females]. HPV vaccines are not licensed for use in male children in India. In children with previously completed immunization there is no data to make any recommendation but single dose may be considered in females.

Bacillus Calmette Guerin (BCG) vaccine [25,28]: BCG vaccine is included in UIP. IAP recommended upper age limit for vaccination is 5 years. It is contraindicated during ongoing chemotherapy and can only be given after 6 months of completion of chemotherapy as a single dose in previously unimmunized children. In children with previously completed immunization with visible scar no further doses are recommended.

Oral Polio Virus vaccine (OPV) [25,28]: OPV is included in UIP. IAP recommended upper age limit for vaccination is 5 years. It is contraindicated during and upto 6 months after chemotherapy including pulse polio immunization days. After 6 months from stoppage of chemotherapy it is recommended to vaccinate children with IPV (see under IPV). When IPV is unavailable bivalent OPV (bOPV), three doses 1 month apart is recommended for unimmunized children. In children with previously completed immunization two doses of bOPV, 1 month apart is recommended if IPV is unavailable. After 6 months of stopping treatment children should be actively encouraged for pulse polio immunisation days.

Measles, Mumps and Rubella (MMR) vaccine [25, 29]: MMR or MR (measles and rubella) is included in UIP. There is no IAP recommended upper age limit for vaccination. MMR vaccine is contraindicated during and up to 6 months after chemotherapy. Ribavirin and intravenous immunoglobulin (IVIg) have been tried for post-exposure prophylaxis of measles during chemotherapy. Recommendation after 6 months of stoppage of chemotherapy in previously unimmunized children is two doses 1 to 3 months apart, whereas single dose is recommended for previously immunized children.

Varicella vaccine [25,8]: Not included in UIP. There is no IAP recommended upper age limit for vaccination. Vaccination with varicella vaccine is contraindicated during ongoing chemotherapy and 6 months thereafter. Following which the schedule is age dependent in unimmunized children (<13 years age - two doses of vaccine >3 months apart, >13 years age - two doses of vaccine >1 months apart) whereas single booster dose is recommended in children with previously completed immunization. Vaccination is not needed in children with history of chicken-pox prior to treatment. Children exposed to varicella infection during ongoing chemotherapy should be given prophylaxis with Varicella Zoster Immunoglobulin (VZIg)/IVIg or oral acyclovir.

Live Attenuated Hepatitis A Vaccine [25]: It is not included in UIP and there is no IAP recommended upper age limit for vaccination. It is contraindicated during ongoing chemotherapy. A single dose for both previously immunized and unimmunized children is recommended after 6 months from stoppage of chemotherapy.

Rotavirus Vaccine [30]: Rotavirus vaccine is not included in UIP. IAP recommended upper age limit for vaccination is 12 months of age. It is contraindicated during ongoing chemotherapy. Generally child outgrows the maximum permissible age for vaccination by 6 months after end of chemotherapy therefore rotavirus vaccine is not indicated.

Influenza vaccine (inactivated) [31-33]: Influenza vaccine is not included in UIP and there is no IAP recommended upper age limit for vaccination. Recommendation during ongoing chemotherapy and up to 1 year after completion of treatment is age dependent (age 6 months to 9 years – two doses one month apart and then single dose every year till indicated, age >9 years – single dose every year till indicated). Vaccination should start as soon as the new vaccine is released and available in the market. The recommended period is just before the onset of the rainy season (before June for most of India and before October for some of the southern states).

After 1 year from the completion of chemotherapy, influenza vaccine is not recommended routinely unless the child continues to have high-risk conditions necessitating influenza vaccination e.g., chronic cardiac, pulmonary, liver and renal disease, diabetes, HIV, etc.

Rabies vaccine (post exposure prophylaxis) [25]: Children with cancer undergoing treatment may mount a significantly lower or no detectable neutralizing antibody response to rabies. In such patients in whom the presence of immunological memory is no longer assured as a result of other causes, proper and thorough wound management and antisepsis accompanied by local infiltration of rabies immunoglobulin followed by anti-rabies vaccination are of utmost importance. Even immunocompromised patients with category II exposures should receive rabies immunoglobulin in addition to a full post-exposure vaccination including the 6th dose on day 90 which is also mandatory.

Tetanus prophylaxis in wound management [25]: All patients presenting with skin wounds/ infections should be evaluated for tetanus prophylaxis. Cleaning of the wound, removal of devitalized tissue, irrigation and drainage is important to prevent anaerobic environment which is conducive to tetanus toxin production.

In a child with cancer who is on treatment and who then gets a wound, it can be assumed that the antibody levels are inadequate. Therefore in a clean, minor wound – Td/TdaP booster regardless of immunization status is recommended, for all other wounds – Td/TdaP + Tetanus Immuno Globulin is advised.

Other vaccines: Other non-live vaccines like Meningococcal vaccine, Japanese encephalitis vaccine, Cholera vaccine and Yellow fever vaccine are not recommended by IAP for routine use in healthy children. They also have no specific role in children with cancer during or after treatment. It is recommended to consult the IAP guide book of immunization to decide whether or not to use these vaccines in specific situations.

Immunization in asplenia/hyposplenia [8,25,28]: In childhood cancer patients, asplenia or hyposplenia may result from radiation therapy involving spleen. Occasionally splenectomy may be part of local control of cancer. These children are at a high risk of serious infection with encapsulated organisms. In addition to routine vaccines, immunization with pneumococcal (both conjugate and polysaccharide), hemophilus influenzae type B, meningococcal and typhoid vaccines are indicated.

If splenectomy is planned, immunization should be initiated at least 2 weeks prior to splenectomy to achieve a superior immunologic response.

Siblings [4,11,23,35]: All non-live vaccines are allowed as per immunisation schedule. Additionally inactivated influenza vaccine is recommended for the siblings. Live vaccines like BCG, MMR, Varicella, Rotavirus and Yellow fever vaccine are also allowed as scheduled. Oral polio virus vaccine is contraindicated including pulse polio immunization days. Sibling should receive IPV and if either is given by mistake or given because of lack of option, then the sibling should remain away from index child for at least 2 weeks.

Varicella vaccine is encouraged in the unimmunized sibling who has not had chicken-pox before and if the sibling develops varicella vaccine induced rash, then the sibling should stay away from index child till all lesions crust.

Rotavirus vaccine is not discouraged but immunocompromised contact (child with cancer) should refrain from changing diapers of the vaccinated infant till 4 weeks from day of vaccination.

Parents [11]: Inactivated Influenza vaccine is strongly recommended varicella vaccine is also encouraged in the unimmunized parent who has not had chicken-pox before and if the parent develops varicella vaccine induced rash, then the parent should stay away from index child.

Contributors: RSA, NRM: conceptualised the guideline. NRM, JC, PM, RSA: a draft guideline was produced. The guideline was discussed in a meeting by nominated representatives of the PHO chapter (NS, SB) and the ACVIP (PJ, SS) of the IAP; NRM, RSA: following the meeting the guideline was modified and circulated amongst the authors (NRM, RSA, PM, JC, NS, SB, PJ and SS); NRM,RSA: The final modifications were made. All the authors approved the final manuscript.

Funding: None; Competing Interests: None stated.

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