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Vacunación antigripal para niños que reciben quimioterapia para el cáncer

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Antecedentes

La infección por influenza es una causa potencial de morbilidad grave en niños con cáncer, por lo que se recomienda la vacunación antigripal. Sin embargo, los datos son contradictorios en cuanto a la respuesta inmunitaria a la vacunación antigripal en niños con cáncer y el valor de la vacunación permanece incierto.

Objetivos

1. Evaluar la eficacia de la vacunación antigripal en la estimulación de una respuesta inmunitaria en niños con cáncer durante la quimioterapia, en comparación con los grupos control.
2. Evaluar la eficacia de la vacunación antigripal en la prevención de la gripe confirmada y la enfermedad similar a la gripe o en la estimulación de la respuesta inmunitaria en niños con cáncer que reciben quimioterapia en comparación con placebo, ninguna intervención o posologías diferentes.
3. Identificar los efectos adversos asociados con las vacunas antigripales en niños con cáncer que reciben quimioterapia, en comparación con otros grupos control.

Métodos de búsqueda

Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trial; CENTRAL), MEDLINE (1966 a 2012), y EMBASE (1980 a 2012) hasta agosto de 2012. También se buscaron, listas de referencias de artículos pertinentes y actas de congresos de la International Society for Paediatric Oncology (SIOP), la Multinational Association of Supportive Care in Cancer (MASCC), la Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) y la Infectious Diseases Society of America (IDSA).

Criterios de selección

Se consideraron los ensayos controlados aleatorios (ECA) y los ensayos clínicos controlados (ECC) en los cuales la respuesta serológica a la vacunación antigripal de los niños con cáncer se comparó con la de grupos control. También se consideraron los ECA y ECC que analizaron los efectos de la vacunación antigripal en la respuesta clínica o inmunitaria en niños con cáncer que reciben quimioterapia, comparada con placebo, ninguna intervención o posologías diferentes.

Obtención y análisis de los datos

Dos autores de la revisión independientes evaluaron la calidad metodológica de los estudios incluidos y extrajeron los datos.

Resultados principales

Se incluyeron un ECA y nueve ensayos clínicos controlados (ECC) (número de participantes = 770). Ninguno de los estudios incluidos presentó medidas de resultado clínicas. Todos los estudios incluidos informaron sobre la inmunidad contra la gripe y las reacciones adversas a la vacunación. En cinco estudios las respuestas inmunitarias a la vacuna antigripal se compararon en 272 niños que recibían quimioterapia y en 166 que no la recibían. En cuatro estudios las respuestas a la vacuna antigripal se evaluaron en 236 niños que recibían quimioterapia, comparadas con las respuestas en 142 niños sanos. Las medidas utilizadas para evaluar la respuesta inmunitaria incluyeron un aumento de cuatro veces en los niveles de anticuerpos después de la vacunación, la aparición de un valor de inhibición de la hemaglutinación (IH) > 32 y los valores de la media geométrica antes y después de la vacunación. Las respuestas inmunitarias en niños que recibían quimioterapia fueron consistentemente más débiles (aumento de cuatro veces de 38% a 65%) que en los niños que completaron la quimioterapia (50% a 86%) y en los niños sanos (53% a 89%). Con respecto a los efectos adversos, 391 pacientes de oncología pediátrica recibieron la vacuna antigripal y los efectos adversos descritos fueron reacciones locales leves y fiebre baja. No se informaron efectos adversos potencialmente mortales ni persistentes.

Conclusiones de los autores

Los pacientes de oncología pediátrica que reciben quimioterapia pueden generar una respuesta inmunitaria a la vacuna antigripal, pero aún está poco claro si esta respuesta inmunitaria los protege de la infección por influenza o de sus complicaciones. Se aguarda por los resultados de ECA bien diseñados que aborden el beneficio clínico de la vacunación antigripal en estos pacientes.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

Vacunación antigripal para niños que reciben quimioterapia para el cáncer

Los niños con cáncer son propensos a contraer infecciones. Una infección víricas es la gripe (influenza). Esta puede cursar de forma inofensiva en estos niños, aunque algunos pueden desarrollar complicaciones graves. Por lo tanto, esta revisión se centra en la eficacia de la vacunación antigripal en niños con cáncer. No se identificaron estudios que evaluaran la eficacia clínica de la vacunación antigripal; sin embargo se identificó un ensayo clínico controlado adicional en la actualización, lo cual da un total de nueve estudios que evaluaron la respuesta inmunitaria después de la vacunación en niños con cáncer. Se indicó que, en los niños que reciben quimioterapia, las respuestas inmunitarias son más deficientes si se les compara con niños sanos, pero que la vacuna se puede administrar sin que se produzcan daños. Según esta revisión actualizada, no es posible recomendar o desalentar la vacunación antigripal en niños con cáncer que reciben quimioterapia. Se recomienda realizar un ensayo futuro que aborde los beneficios clínicos de la vacunación antigripal en niños con cáncer que reciben quimioterapia.

Authors' conclusions

Implications for practice

In national guidelines, it is recommended that children who are being treated for cancer should be vaccinated against influenza. Clinical evidence from randomised controlled studies to support this recommendation is lacking. It has been shown in the trials included in this review that these patients are able to generate an immune response to influenza vaccine, but it remains unclear whether this immune response protects them from influenza infection or its complications. Influenza vaccination appears to be safe in these children. Clinicians must consider the benefits and risks of influenza vaccination in children with cancer, while awaiting results from randomised controlled trials addressing the clinical benefit of influenza vaccination in these patients.

Implications for research

To evaluate clinical outcome, a well‐designed prospective, multi‐centre, randomised controlled trial of influenza vaccination in children being treated for cancer is necessary. This trial should have a minimal risk of bias and should carefully define and measure clinically relevant outcomes, including laboratory‐confirmed influenza infection, pneumonia, hospitalisation and mortality. It should be realised that many practical difficulties are involved in conducting such a trial. Many participants would have to be included as the incidence of influenza is fairly low, particularly in non‐epidemic years. The effectiveness of the vaccine is best determined during epidemic years in which a good match between the vaccine and circulating strains exists. However, the degree of matching is not known until the influenza season starts, and by this time the trial should already have begun. Also, a diagnosis of laboratory‐confirmed influenza may be difficult to achieve as paediatric oncology patients may receive supportive care in centres other than their primary oncology centre. Only when such a trial has been conducted can evidence‐based judgements on the value of influenza vaccine in these children be made. We welcome suggestions on all aspects of such a multi‐centre trial, as well as potential participating centres.

Background

Advances in the diagnosis and treatment of opportunistic viral infections have led to the discovery that common community‐acquired respiratory viruses are major pathogens associated with significant morbidity and mortality in immunocompromised or chronically ill patient populations (Hicks 2003). In oncology patients, the main risk factor associated with viral infection is disruption of the cellular immune response. The duration and severity of chemotherapy‐induced neutropenia are of lesser importance (Sandherr 2006). It has been shown that in 30% to 60% of immunocompromised patients with a diagnosis of idiopathic pneumonia (clinical or radiological findings in accordance with pneumonia), the condition is caused by viruses among which influenza is a major contributor (Hicks 2003).

Influenza virus infection occurs in yearly epidemics. An influenza epidemic may last five to six weeks and can be associated with attack rates as high as 20% in the general population, and possibly higher in the immunocompromised population. In patients who are hospitalised (mainly elderly and immunocompromised patients), nosocomial transmission rates reach 55% to 83% (Dykewicz 2001; Raad 1997). Paediatric oncology patients are highly susceptible to influenza infection (Chisholm 2001), have an increased rate of influenza infection compared with healthy controls and may have prolonged influenza infections compared with healthy controls (Feldman 1977; Kempe 1989). Although the illness usually runs a mild course in children with cancer, it may result in hospitalisation, interruption of chemotherapy and administration of antibiotics. Severe and fatal complications involving mainly secondary infections and haemophagocytic syndromes have been reported in paediatric oncology patients with influenza infection (Feldman 1977; Kempe 1989; Potter 1991).

The mainstay of influenza prophylaxis in the general population is vaccination. It is safe and immunogenic and shows 70% to 90% efficacy in preventing influenza when a good antigenic match exists between the vaccine and the epidemic virus (Hicks 2003). According to the 2010 guidelines of the Advisory Committee on Immunization Practices (ACIP) (Fiore 2010) used in the USA, vaccination with the inactivated influenza vaccine is recommended for the following groups, who are at increased risk of complications from influenza: (1) all children aged 6 months to 5 years (59 months); (2) all persons aged > 50 years; (3) adults and children who have chronic pulmonary (including asthma) or cardiovascular (except isolated hypertension), renal, hepatic, neurological, hematological, or metabolic disorders (including diabetes mellitus); (4) persons who have immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus (HIV)); (5) women who are or will be pregnant during the influenza season; (6) children and adolescents (aged 6 months to 18 years) who are receiving long‐term aspirin therapy and who might be at risk for experiencing Reye syndrome after influenza virus infection; (7) residents of nursing homes and other long‐term‐care facilities; (8) American Indians/Alaskan Natives; (9) persons who are morbidly obese (body mass index (BMI) > 40); (10) health care professionals (HCPs); (11) household contacts and caregivers of children aged < 5 years and adults aged > 50 years, with particular emphasis on vaccinating contacts of children aged < 6 months; and (12) household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza (Fiore 2010).

The inactivated vaccine involves no risk of introducing active infection, and it is regarded as safe in immunocompromised individuals, even in paediatric oncology patients. Defects involving both cell‐mediated and humoral immunity frequently accompany malignancies, and chemotherapy induces myelosuppression, so that suboptimal responses to vaccination might be expected in patients with malignant disease. Immunological responses are generally less than expected in healthy persons and may depend on the timing of vaccination relative to chemotherapy. However, a paucity of data is available for paediatric oncology patients, and the patient groups are heterogeneous with regard to underlying malignancy, chemotherapeutic regimens and the type, dose, timing and route of administration of influenza vaccines. Antibody levels considered protective in healthy individuals may not prevent clinical infection in those with malignant disease (Ring 2002). This is an update of the first systematic review (Goossen 2009) undertaken to evaluate the state of evidence on the efficacy of influenza vaccination in paediatric oncology patients treated with chemotherapy. We systematically reviewed all data ‐ not only clinical consequences (including adverse effects), but also immunological responses.

Objectives

  1. To assess the efficacy of influenza vaccination in stimulating an immunological response in children with cancer during chemotherapy, compared with control groups.

  2. To assess the efficacy of influenza vaccination in preventing confirmed influenza and influenza‐like illness and/or in stimulating immunological response in children with cancer treated with chemotherapy, compared with placebo, no intervention or different dosage schedules .

  3. To identify the adverse effects associated with influenza vaccines in children with cancer treated with chemotherapy, compared with other control groups.

Methods

Criteria for considering studies for this review

Types of studies

We considered randomised controlled trials (RCTs) and controlled clinical trials (CCTs) in which the serological response to influenza vaccination of children with cancer was compared with that of control groups. We also considered RCTs and CCTs that compared the effects of influenza vaccination on influenza and/or influenza‐like illness and/or stimulated immunological response in children with cancer being treated with chemotherapy, compared with placebo, no intervention or different dosage schedules.

Types of participants

Children with cancer (1 to 18 years of age) who are being treated with chemotherapy or who have been off chemotherapy for less than one month.

Types of interventions

Vaccination with any influenza vaccine, in any dose, preparation or time schedule.

Types of outcome measures

  • Laboratory‐confirmed influenza infection.

  • Influenza‐like illness (as defined by the authors; most often non‐specific respiratory illness characterised by fever, fatigue and cough) with or without one of the following complications:

    • Pneumonia (radiographically documented, clinically diagnosed) or any secondary infection.

    • Hospitalisation.

    • Days in intensive care unit (ICU).

    • Delay in chemotherapy.

    • Mortality.

  • Influenza immunity (difference in pre‐ and post‐influenza vaccination haemagglutinin inhibition antibody titre).

  • Adverse reactions related to influenza vaccination (such as arm soreness, fever, myalgia, fatigue, malaise or headache).

Search methods for identification of studies

We searched the following electronic databases to identify reports: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, issue 1, for the original review; and The Cochrane Library 2012, issue 8, for the update), MEDLINE/PubMed (from 1966 to February 2007 for the original review; and to August 2012 for the update) and EMBASE/Ovid (1980 to February 2007 for the original review; and to August 2012 for the update). We used the subject headings and text words shown in Appendix 1, Appendix 2 and Appendix 3.

We located information on trials not registered in CENTRAL, MEDLINE or EMBASE, published or unpublished, by searching the reference lists of relevant articles and review articles. We scanned, electronically if available and otherwise by handsearching, the ten latest issues (2001 to 2006 for the original review; and 2007 to 2011 for the update) of the conference proceedings of the International Society of Paediatric Oncology (SIOP), the Multinational Association of Supportive Care in Cancer (MASCC), the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Diseases Society of America (IDSA). We also contacted researchers involved in this clinical area, and we applied no language restrictions in our search.

Data collection and analysis

Selection of studies

Two review authors (GMG and MDvdW) independently identified studies that met the eligibility criteria. The Methods section of the trial served as the basis for our decisions on which trials to include in this systematic review update. We resolved discrepancies by discussion. If this approach was unsuccessful, arbitration by a third party was obtained. We clearly stated reasons for exclusion of any study considered in this review process.

Data extraction and management

The two review authors (GMG and MDvdW) independently performed data extraction using standardised forms. We extracted data on the characteristics of participants (age, sex, tumour type and anti‐cancer treatment received), interventions (description of vaccine, dose and timing and route of delivery of vaccine), outcome measures (immunological response to vaccination, laboratory‐confirmed influenza, influenza‐like illness, pneumonia or any secondary infection, cases of influenza admitted to hospital, days in ICU, delay to chemotherapy, mortality and adverse events related to influenza vaccine), length of follow‐up and study design. In cases of disagreement, we reexamined and discussed the abstracts and articles until consensus was achieved. When data were missing, we made an attempt to contact the study authors for additional information. We obtained extra information on one study (Chisholm 2005), including (1) the protective response rate, the seroresponse rate and the geometric mean titre (GMT) for each of the three viral strains four to six weeks after final vaccination in children on chemotherapy and (2) the protective response rate, the seroresponse rate and the GMT for each of the three viral strains four to six weeks after final vaccination in children off chemotherapy. We entered the data into RevMan 5 software (RevMan 2008).

Assessment of risk of bias in included studies

The two review authors independently assessed trial quality. We assessed the methodological quality of the RCTs in accordance with the guidelines recommended by the Cochrane Childhood Cancer Group at the time of the original version of the review (see Table 1). We used the Newcastle‐Ottawa Scale (NOS 2007) for quality assessment of CCTs (see Table 2) and contacted study authors for additional information where necessary. Disagreements were resolved by discussion between the review authors.

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Table 1. Cochrane Childhood Cancer Group guidelines on quality assessment of randomised controlled trials

Assessment of methodological quality of randomised controlled trials

Selection bias
Allocation concealment:
A. Adequate: use of randomisation method that did not allow investigator and participant to know or influence the allocation of treatment before eligible participants entered the study
B. Unclear: randomisation stated but no information on method used is available
C. Inadequate: use of alternate medical record numbers or unsealed envelopes as randomisation method, and/or information in the study indicates that investigators or participants could have influenced the allocation of treatment

Performance bias
Blinding of care providers: yes/no/unclear
Blinding of participants: yes/no/unclear
Care providers and participants are considered not blinded if the intervention group can be identified in > 20% of participants because of side effects of treatment

Detection bias
Blinding of outcome assessors: yes/no/unclear

Attrition bias
Intention‐to‐treat analysis:
A. Yes: all participants analysed in the treatment group to which they were allocated, regardless of whether or not they received the allocated intervention
B. No: some participants (< 5%, 5% to 10%, 10% to 20%, > 20%) not analysed in the treatment group to which they were randomly assigned because they did not receive the study intervention or they withdrew from the study, or because of a protocol violation
C. Unclear: inability to determine whether participants were analysed according to the intention‐to‐treat principle after contact with the authors

Completeness of follow‐up
Percentage of participants excluded or lost to follow‐up for the different treatment groups for primary and secondary outcomes (< 5%, 5% to 10%, 10% to 20%, > 20%)

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Table 2. Newcastle‐Ottawa quality assessment scale

Scale

Cohort studies

Note: A study can be awarded a maximum of 1 star for each numbered item within the Selection and Outcome categories. A maximum of 2 stars can be given for Comparability. A total of 9 stars can be awarded.

Selection
1. Representativeness of the exposed cohort (1 star*)
a) Truly representative of the exposed cohort
b) Somewhat representative of the exposed cohort
c) Selected group of users, e.g. nurses, volunteers
d) No description of the derivation of the cohort

2. Selection of the non‐exposed cohort (1 star*)
a) Drawn from the same community as the exposed cohort
b) Drawn from a different source
c) No description of the derivation of the non‐exposed cohort

3. Ascertainment of exposure (1 star*)
a) Secure record
b) Structured interview
c) Written self‐report
d) No description

4. Demonstration that outcome of interest was not present at start of study (1 star*)
a) Yes
b) No

Comparability
1. Comparability of cohorts on the basis of the design or analysis (max 2 stars**)
a) Study controls for age
b) Study controls for time on chemotherapy

Outcome (1 star*)
1. Assessment of outcome
a) Independent blind assessment
b) Record linkage
c) Self‐report
d) No description

2. Was follow‐up long enough for outcomes to occur? (1 star*)
(1) Yes
(2) No

3. Adequacy of follow‐up of cohorts (1 star*)
a) Complete follow‐up ‐ all participants accounted for
b) Participants lost to follow‐up unlikely to introduce bias ‐ small number lost > 80% follow‐up
c) Follow‐up rate < 80% and no description of those lost
d) No statement

Data synthesis

We analysed the data according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane Handbook). We analysed non‐randomised trials separately and described the study results separately in the Results section. The results are presented as described by the authors. Some investigators used an intention‐to‐treat analysis; others did not. Pooling of data was not possible because different study groups and different vaccines were described in the included studies.

Results

Description of studies

After performing searches of the electronic databases the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed and EMBASE/Ovid (in February 2007), we identified 3172 titles of reports of potentially relevant studies, which we screened for retrieval. We excluded 3136 reports by screening titles and abstracts. We then retrieved 36 reports for detailed assessment; a further 28 were then excluded. After searching the conference proceedings and reference lists of relevant studies and reviews, we identified nine additional reports for detailed assessment. None of these were included. A complete list with reasons for exclusion is presented in the table of 'Characteristics of excluded studies' (n = 36). One of the excluded studies (Bektas 2007) was mentioned as an ongoing study in the original review (Karadeniz 2005). Thus, we included eight studies (total number of participants of 708) from the original systematic review.

Running searches for the update in CENTRAL, MEDLINE/PubMed and EMBASE/Ovid (in August 2012) yielded a total of 598 new references. After screening titles, abstracts or both, we excluded 595 references that clearly did not meet all inclusion criteria for this review. We retrieved three reports for detailed assessment, of which two were excluded (Esposito 2009; Reilly 2010; see the 'Characteristics of excluded studies' table for the exact reason).

Upon scanning the reference lists of relevant studies and reviews as well as conference proceedings, we did not identify any eligible studies. We identified no eligible ongoing studies by scanning the ongoing trials databases.

In the update of August 2012, one study was included (total number of participants in this study was 62). In total (original review and update), nine studies were included in this current update with a total number of participants of 770.

Included studies

Characteristics of the nine included studies are presented in the table 'Characteristics of included studies'. One of the studies comprised both an RCT (Hsieh 2002a) and a CCT (Hsieh 2002b). All of the remaining eight studies were CCTs; thus one RCT and nine CCTs were included. None of the included studies compared influenza vaccine with placebo, and no clinical outcomes of influenza infection were assessed. In five of these studies (Chisholm 2005; Gross 1978; Lange 1979; Matsuzaki 2005; Steinherz 1980), responses to different strains of influenza vaccine, in a total of 272 children with cancer receiving chemotherapy, were compared with those of 166 children with cancer not receiving chemotherapy during the four weeks before vaccination. In four studies (Lange 1979; Porter 2004; Shahgholi 2010; Steinherz 1980), responses to different strains of influenza vaccine in a total of 236 children with cancer receiving chemotherapy were compared with those in 142 healthy children. In one study, responses to different strains of influenza vaccine in 25 children receiving maintenance chemotherapy for acute lymphoblastic leukaemia (ALL) were compared with those in 30 children with asthma in remission (Hsieh 2002b). Furthermore, two vaccination protocols were compared in a total of 25 children with ALL on maintenance chemotherapy (Hsieh 2002a). In one study (Chisholm 2001), serology of 42 immunised paediatric oncology participants was compared with that of 42 non‐immunised paediatric oncology participants.

Risk of bias in included studies

Data on quality assessment of the eight included CCTs are shown in Table 3. The CCTs were of almost equal quality scoring. Each scored between seven and nine stars, when the maximum possible was nine.

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Table 3. Quality of included CCTs

Selection

Comparability

Outcome

Total

Chisholm 2001

4 stars (classified A)

1 star

2 stars (poor follow‐up) classified as B

7 stars

Chisholm 2005

4 stars (classified A)

1 star

2 stars (poor follow‐up) classified as B

7 stars

Gross 1978

4 stars (classified A)

2 stars

3 stars

9 stars

Hsieh 2002a

4 stars (classified A)

2 stars

3 stars

9 stars

Lange 1979

4 stars (classified A)

2 stars

2 stars (poor follow‐up) classified as B

8 stars

Matsuzaki 2005

4 stars (classified A)

2 stars

3 stars

9 stars

Porter 2004

4 stars (classified A)

2 stars

2 stars (poor follow‐up) classified as B

8 stars

Shahgholi 2010

4 stars (classified A)

2 stars

2 stars (poor follow‐up of adverse events

classified as B)

8 stars

Steinherz 1980

4 stars (classified A)

1 star

2 stars (poor follow‐up) classified as B

7 stars

Six of the included studies did not have a complete follow‐up (Chisholm 2001; Chisholm 2005; Lange 1979; Porter 2004; Shahgholi 2010; Steinherz 1980). In two of these studies (Chisholm 2005; Porter 2004), the number of participants lost to follow‐up was small and was unlikely to introduce bias. In one study (Shahgholi 2010), data on adverse reactions were available for only 56% of participants. No loss to follow‐up was reported for other outcomes. In the remaining studies, a large percentage of participants was lost to follow‐up, respectively, 36% of non‐immunised participants in Chisholm 2001, 29% of participants receiving chemotherapy in Lange 1979 and 52% of participants receiving chemotherapy in Steinherz 1980. These three studies are susceptible to attrition bias because loss to follow‐up is greater than 20%. Reasons for loss to follow‐up were stated in Chisholm 2001 and Steinherz 1980. In Lange 1979, reasons for loss to follow‐up were not stated. However, the high percentage of loss to follow‐up is noted at 12 months after the first vaccination, althoughoutcomes relevant to this review are assessed one month after the last vaccination. Loss to follow‐up one month after the last vaccination was less than 20%.

Ages of children in the different groups (i.e. children receiving chemotherapy, children not receiving chemotherapy and healthy children) were comparable, except in three studies (Chisholm 2001; Chisholm 2005; Steinherz 1980). In two of these (Chisholm 2001; Chisholm 2005), the mean age or range of age of the children is not stated. In the other study (Steinherz 1980), children receiving chemotherapy were about three years younger than those off chemotherapy. Age is a possible confounder for immune response.

In the one included RCT (Hsieh 2002a) (Table 4), the method of randomisation was not stated, allocation concealment and blinding of care providers was unclear and no blinding of participants was performed. This makes the trial susceptible to bias.

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Table 4. Quality of RCT

Scored items

Hsieh 2002

Randomisation performed

Yes, method not stated

Allocation concealment

Unclear

Blinding of care providers

Unclear

Blinding of participants

No

Blinding of outcome assessors

Yes

Intention‐to‐treat analysis

Yes

Completeness of follow‐up

None lost to follow‐up

Attempts to gain additional information from the study authors regarding methodological quality met with some success. We obtained additional data from the author of one study (Chisholm 2005).

Effects of interventions

Because pooling was not possible, we present only descriptive results.

Outcomes

  • Laboratory‐confirmed influenza infection within the epidemic period

This was not reported as an outcome measure in any of the included studies. In one study (Matsuzaki 2005), it is mentioned in the results section that none of the participants who received two doses of influenza vaccine were diagnosed as having influenza during the following influenza season. However, it is not stated what methods were used to identify influenza infection.

  • Influenza‐like illness, pneumonia, hospitalisation, days in ICU, delay in chemotherapy and mortality

These were not reported as outcome measures in any of the included studies.

  • Influenza immunity (difference in pre‐ and post‐influenza vaccination haemagglutinin inhibition (HI) antibody titre)

Various measures were used to assess immune response after vaccination. Five studies (Chisholm 2005; Hsieh 2002a; Matsuzaki 2005; Porter 2004; Steinherz 1980) assessed a four‐fold rise in antibody titre after vaccination. Seven studies defined as protective the development of haemagglutination inhibition (HI) antibody titre of > 32 (Chisholm 2005; Steinherz 1980) or > 40 (Chisholm 2001; Gross 1978; Hsieh 2002b; Matsuzaki 2005; Shahgholi 2010) after vaccination. In seven studies (Chisholm 2001; Chisholm 2005; Gross 1978; Hsieh 2002b; Lange 1979; Porter 2004; Shahgholi 2010), pre‐ and post‐vaccination GMTs were provided. These results have been summarised in the following comparisons.

  • Adverse effects

See later.

Comparisons related to objective 1: the efficacy of influenza vaccination in children with cancer during chemotherapy compared with other control groups

Comparison 01: influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated children off chemotherapy

Five studies (Chisholm 2005; Gross 1978; Lange 1979; Matsuzaki 2005; Steinherz 1980) reported on this comparison. Results on protective HI titre, four‐fold rise in antibody titre and pre‐ and post‐vaccination GMTs are presented in Analysis 1.1 to Analysis 1.3. Immune responses to influenza vaccine in children receiving chemotherapy were weaker than those in children who completed chemotherapy in four studies (Gross 1978; Lange 1979; Matsuzaki 2005; Steinherz 1980). As is demonstrated in Analysis 1.1, this is not true for all tested influenza strains. Within two studies (Matsuzaki 2005; Steinherz 1980), one influenza strain showed comparable results in children receiving chemotherapy compared with children off chemotherapy. In another study, comparable immune responses were found for all three influenza strains, after extra information was obtained from the author (Chisholm 2005).

Comparison 02: influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated healthy children

Four studies (Lange 1979; Porter 2004; Shahgholi 2010; Steinherz 1980) reported on this comparison. Results on four‐fold rise in antibody titre and pre‐and post‐vaccination GMTs are presented in Analysis 2.1 and Analysis 2.2. Immune responses in children receiving chemotherapy were weaker than those in healthy children. After vaccination, 38% to 65% of children receiving chemotherapy had a four‐fold rise in antibody titre compared with 53% to 89% of healthy children, but no significance was reached except in three influenza strains. One influenza strain was included in the Porter study and two in the Shahgholi study, in which children receiving chemotherapy had a significantly weaker immune response to influenza vaccination when compared with healthy children (Porter 2004; Shahgholi 2010). Healthy children showed significantly higher GMTs after vaccination than were noted in those receiving chemotherapy for all three strains in the Porter study (Porter 2004) and for one strain in the Shahgholi study (Shahgholi 2010). This finding was not reported in the study of Lange et al (Lange 1979).

Comparison 03: influenza immunity in vaccinated children with acute lymphoblastic leukaemia (ALL) receiving chemotherapy compared with vaccinated children with asthma

One study (Hsieh 2002b) reported on this comparison. Results on seroconversion, seroprotection and pre‐ and post‐vaccination GMT are presented in Analysis 3.1 to Analysis 3.3. Immune responses in children receiving chemotherapy were weaker than those in children with asthma. After vaccination, 24% to 60% of children with ALL developed a four‐fold rise in antibody titre compared with 63% to 77% of children with asthma, and 57% to 85% compared with 73% to 90% developed protective HI titres. After vaccination, children with asthma showed higher GMTs than those with ALL. It is noteworthy that a higher percentage of children with ALL developed protective antibody titres against the A/Pan/2007/99 viral strain: 85% compared with 73% of children with asthma; therefore no difference in immune response was noted between the two groups using this strain.

Comparisons related to objective 2: the efficacy of influenza vaccination compared with placebo, no intervention or different dosage schedules in children with cancer treated with chemotherapy

Comparison 04: influenza immunity in vaccinated compared with non‐vaccinated paediatric oncology participants

One study (Chisholm 2001) reported on this comparison. Results on seroprotection and pre‐ and post‐vaccination GMT in the immunised group are presented in Analysis 4.1 and Analysis 4.2. After vaccination, a significant rise in GMT was reported, and 48% to 70% of immunised children developed protective HI titres after vaccination. A comparison with the non‐immunised group cannot be made because information on GMTs and achieving protective titres in this group is missing.

Comparison 05: influenza immunity in two vaccination schedules in children with ALL receiving maintenance chemotherapy

One study (Hsieh 2002a) reported on this comparison (Analysis 5.1; Analysis 5.2). Two vaccination protocols were compared in children with ALL receiving maintenance chemotherapy. One group received the first dose of vaccine on the same day as the scheduled reinduction chemotherapy and the second dose four weeks later. The other group received the first dose of vaccine without chemotherapy and the second dose on the same day as the reinduction chemotherapy. Comparable rates in four‐fold antibody rise and achieving protective antibody titres were found in both vaccination protocols, and no significant difference was reported.

Adverse reactions related to influenza vaccination (such as arm soreness, fever, myalgias, fatigue, malaise, headache)

In the included studies, a total of 391 paediatric oncology participants who were being treated with chemotherapy received influenza vaccine. In all of the included studies, a statement was made concerning adverse effects after vaccination. Eight studies (Chisholm 2005; Gross 1978; Hsieh 2002a; Hsieh 2002b; Lange 1979; Porter 2004; Shahgholi 2010; Steinherz 1980) described the procedure that was used for assessment of adverse effects. Assessment of outcomes in these studies was performed most often by parents.

No reports described life‐threatening or persistent adverse effects. The studies reported "occasional" mild local reactions and low‐grade fever (Lange 1979; Steinherz 1980; Shahgholi 2010 (last study not complete data for adverse events)). The number and severity of adverse reactions after vaccination in the children receiving chemotherapy and in the healthy controls did not differ significantly (Porter 2004; Shahgholi 2010 (last study not complete data for adverse events)). In one study, participants receiving chemotherapy were less likely to experience adverse reactions than participants off chemotherapy (Gross 1978). Participants receiving chemotherapy had a higher incidence of malaise and poor appetite than did those with asthma after vaccination (Hsieh 2002b). Participants with asthma were more likely to report local pain and had more episodes of fever in the days after vaccination. One study reported upper respiratory tract symptoms and fever after vaccination in a paediatric oncology participant, requiring oral antibiotics (Chisholm 2005).

Discussion

This is an update of the first systematic review on the effectiveness of influenza vaccination in children being treated for cancer. We have identified a total of nine CCTs and one RCT that were extracted from nine studies fulfilling our inclusion criteria. Unfortunately, no available study compares influenza vaccine with placebo in children being treated for cancer. Furthermore, none of the included studies have reported on clinical outcome measures, such as confirmed influenza during the influenza season, hospitalisation, delay in chemotherapy and mortality. All included studies reported on the outcome measures of influenza immunity and adverse reactions to vaccination.

The included studies demonstrated that paediatric oncology participants receiving chemotherapy were able to generate an immune response to influenza vaccine. However, they had weaker immune responses compared with healthy children, children with asthma or paediatric oncology participants who had completed chemotherapy more than one month before vaccination. Immune responses of the latter were comparable with those of healthy children. The differences in immune response between these groups were noted, irrespective of the method used to assess the immune response (i.e. four‐fold rise in antibody titre, seroprotection or pre‐ and post‐vaccination GMT) and irrespective of the type of malignancy. The difference in response between these groups is most likely explained by immunosuppression, as much from chemotherapeutic agents as from the malignancy as such. Only one study found comparable immune responses in participants with solid tumours receiving chemotherapy compared with participants off chemotherapy (Chisholm 2005). The differences might be that solid tumours, not haematological malignancies, were studied, and that the control group was very small compared with the experimental group.

In reports of influenza vaccination in paediatric oncology participants, it is often stated that data are conflicting regarding the immune response to influenza vaccination, as some studies reveal a sufficient immune response but others fail to do so (Gross 1978; Hsieh 2002a; Lange 1979; Matsuzaki 2005; Porter 2004). This can be explained by a difference in participant populations in these studies. A more sufficient immune response is generally found in studies in which most of the children had completed chemotherapy longer than one month ago. Because the objective of this review was to evaluate response in children receiving chemotherapy, the aforementioned studies were excluded.

Influenza vaccine was safely administered to paediatric oncology participants in the included studies. Adverse effect outcomes were most often assessed by parents; therefore the studies were susceptible to detection bias. No reports described life‐threatening or persistent adverse reactions in any of the included studies. However, it should be noted that children can develop fever in response to vaccination, and in such a case administration of antibiotics may be required in children with cancer. Participants receiving chemotherapy had a higher incidence of malaise and poor appetite after vaccination than did those with asthma (Hsieh 2002b). However, patients receiving chemotherapy are known to experience these symptoms frequently as a consequence of their treatment (Collins 2000).

The immune response generated by influenza vaccination in children with cancer may reduce the risk of influenza infection in these children. However, as has been mentioned, none of the studies included in this review reported on clinical outcome measures. It is not known whether the antibody titres achieved after vaccination are effective in protecting these children from influenza infection and its complications during the following influenza season or in decreasing the severity of such infection. Therefore, the question of whether influenza vaccination is clinically beneficial for paediatric oncology patients receiving chemotherapy remains unanswered.

Limitations

The included studies used different immunisation schedules (according to guidelines from Japan, UK and USA), routes of administration (subcutaneous and intramuscular) and dosages. The results of the studies using different vaccinations were comparable. However, this could not be verified by statistical analysis, as no meta‐analysis could be carried out because of the lack of included RCTs.

All children in the different studies were younger than 18 years of age. Ages of children in the different groups (i.e. children receiving chemotherapy, children not receiving chemotherapy and healthy children) were comparable, except in three studies (Chisholm 2001; Chisholm 2005; Steinherz 1980). In two of these (Chisholm 2001; Chisholm 2005), the mean age or the range of age of the children is not stated. In the other study (Steinherz 1980), children receiving chemotherapy were about three years younger than those off chemotherapy. Age is a possible confounder for immune response.

The included studies had relatively small sample sizes. The results described are all based on separate small studies. Larger trials are needed to verify the results of these studies.

Study

Influenza strain

On chemotherapy n%

On chemotherapy Total N

Off chemotherapy n%

Off chemotherapy Total N

P‐value

Chisholm 2005

A/NC/20/99

16 (42%)

38

3 (43%)

7

1.00

Chisholm 2005

A/PAN/2007/99

12 (50%)

24

2 (40%)

5

0.70

Chisholm 2005

B/Sichuan 379 99

26 (49%)

53

3 (33%)

9

0.48

Gross 1978

A/NJ/76

20 (29%)

68

63 (85%)

74

< 0.001

Gross 1978

A/Vic/75

33 (49%)

68

65 (88%)

74

< 0.01

Gross 1978

Matsuzaki 2005

A/NC/20/99

5 (42%)

12

18 (90%)

20

0.006

Matsuzaki 2005

A/PAN/2007/99

2 (25%)

8

10 (83%)

12

0.019

Matsuzaki 2005

B/Sha/7/97

5 (29%)

17

11 (44%)

25

0.518

Steinherz 1980

A/NJ/76

13 (26%)

50

12 (57%)

21

< 0.05

Steinherz 1980

A/Vic/75

31 (61%)

50

16 (75%)

21

0.380

Steinherz 1980

Figuras y tablas -
Analysis 1.1

Comparison 1 Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated children not receiving chemotherapy, Outcome 1 Number of participants achieving protective titre post‐vaccination (> 32 or 40) after last immunisation.

Study

Influenza strain

On chemotherapy n%

On chemotherapy Total N

Off chemotherapy n%

Off chemotherapy Total N

P‐value

Chisholm 2005

A/NC/20/99

30 (53%)

56

4 (44%)

9

0.13

Chisholm 2005

A/PAN/2007/99

19 (34%)

56

3 (33%')

9

0.85

Chisholm 2005

B/Sichuan 379 99

28 (50%)

56

5 (55%)

9

0.86

Matsuzaki 2005

A/NC/20/99

6 (38%)

16

20 (83%)

24

0.004

Matsuzaki 2005

A/PAN/2007/99

4 (25%)

16

12 (50%)

24

0.105

Matsuzaki 2005

B/Shan/7/97

6 (33%)

18

14 (54%)

26

0.227

Steinherz 1980

A/NJ/76

19 (38%)

50

16 (76%)

21

< 0.01

Steinherz 1980

A/Vic/75

26 (52%)

50

18 (86%)

21

< 0.05

Steinherz 1980

Figuras y tablas -
Analysis 1.2

Comparison 1 Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated children not receiving chemotherapy, Outcome 2 Number of participants with four‐fold rise in antibody titre after last immunisation.

Study

Influenza strain

On chemotherapy GMT pre‐vaccination

On chemotherapy GMT post‐vaccination

Off chemotherapy GMT pre‐vaccination

Off chemotherapy GMT post‐vaccination

P‐value

Chisholm 2005

A/NC/20/99

< 8‐16

290

< 8‐16

284

1.00

Chisholm 2005

A/PAN/2007/99

< 8‐16

87.2

< 8‐16

148

0.30

Chisholm 2005

B/Sichuan 379 99

<8

65.3

<8

72

0.84

Gross 1978

A/NJ/76

0

14

5

84*

< 0.001

Gross 1978

A/Vic/75

11

23

17

133*

< 0.01

Gross 1978

Lange 1979

A/NJ/76

< 8

37.74 ± 1.28

< 8

176.88 ±1.14

< 0.01

Lange 1979

A/Vic/75

10.62 ± 1.14

61.92 ±1.26

12.88 ± 1.15

203,19 ±1.26

< 0.01

Lange 1979

Figuras y tablas -
Analysis 1.3

Comparison 1 Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated children not receiving chemotherapy, Outcome 3 Geometric mean titre (GMTs) pre‐ and post‐vaccination.

Study

Influenza strain

On chemotherapy n%

On chemotherapy

Total N

Healthy n%

Healthy

Total N

P‐value

Porter 2004

A/NC/20/99

13 (65%)

20

41 (89%)

46

P = 0.034

Porter 2004

A/PAN/2007/99

13 (65%)

20

36 (78%)

46

P = 0.258

Porter 2004

B/Vic/504/2000

12 (60%)

20

35 (76%)

46

P = 0.185

Shahgholi 2010

A/SI 3/2006

18 (56,2%)

32

24 (80%)

30

P = 0.04

Shahgholi 2010

A/Wis/67/2005

13 (40,6%)

32

16 (53,3%)

30

P = 0.31

Shahgholi 2010

B/Mal/2506/2004

19 (59,4%)

32

25 (83,3%)

30

P = 0.038

Steinherz 1980

A/NJ/76

19 (38%)

50

5 (71%)

7

P = 0.204

Steinherz 1980

A/Vic/75

26 (52%)

50

6 (86%)

7

P = 0.202

Steinherz 1980

Figuras y tablas -
Analysis 2.1

Comparison 2 Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated healthy children, Outcome 1 Number of participants with four‐fold rise in antibody titre after last immunisation.

Study

Influenza strain

On chemotherapy GMT pre‐vaccination

On chemotherapy GMT post‐vaccination

Healthy GMT pre‐vaccination

Healthy GMT post‐vaccination

P‐value

Lange 1979

A/NJ/76

<8 ± 0.00

37.74 ± 1.28

<8 ± 0.00

52.39 ± 1.13

0.53

Lange 1979

A/Vic/75

10.62 ± 1.14

61.92 ±1.26

12.51 ±1.12

70.34 ± 1.12

0.80

Lange 1979

Porter 2004

A/NC/20/99

6.50

53.82

15.06

367.03

< 0.001

Porter 2004

A/Pan/2007/99

29.86

152.22

72.20

577.59

< 0.03

Porter 2004

B/Vic/504/2000

8.57

39.4

13.15

165.37

< 0.003

Shahgholi 2010

A/SI 3/2006

32,5

52,87

31,5

76,38

0,13

Shahgholi 2010

A/Wis/67/2005

54

81,87

54

145,41

0.04

Shahgholi 2010

B/Mal/2506/2004

12,8

25,41

17

38.07

0.10

Figuras y tablas -
Analysis 2.2

Comparison 2 Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated healthy children, Outcome 2 Geometric mean titre (GMTs) pre‐ and post‐vaccination.

Study

Influenza strain

ALL on chemotherapy n%

ALL on chemotherapy

Total N

Asthma n%

Asthma

Total N

P‐value

Hsieh 2002a

A/NC/20/99

6 (24%)

25

23 (77%)

30

P < 0.0001

Hsieh 2002a

A/Pan/2007/99

15 (60%)

25

19 (63%)

30

P = 0.980
NS

Hsieh 2002a

B/Yam/166/98

11 (44%)

25

20 (67%)

30

P = 0.157

Figuras y tablas -
Analysis 3.1

Comparison 3 Influenza immunity in vaccinated children with ALL receiving chemotherapy compared with vaccinated children with asthma, Outcome 1 Number of participants with four‐fold rise in antibody titre 4 weeks after the last immunisation.

Study

Influenza strain

ALL on chemotherapy n%

ALL group

Total N

Asthma %n

Asthma

Total N

P‐value

Hsieh 2002a

A/NC/20/99

6 (60%)

10

9 (90%)

10

P = 0.302

Hsieh 2002a

A/PAN/2007/99

11 (85%)

13

8 (73%)

11

P = 0.834

Hsieh 2002a

B/Yam/166/98

8 (57%)

14

10 (83%)

12

P = 0.309

Figuras y tablas -
Analysis 3.2

Comparison 3 Influenza immunity in vaccinated children with ALL receiving chemotherapy compared with vaccinated children with asthma, Outcome 2 Number of participants achieving protective titre post‐vaccination (> 40) after last immunisation.

Study

Influenza strain

ALL GMT pre‐vaccination

ALL GMT post‐vaccination

Asthma GMT pre‐vaccination

Asthma GMT post‐vaccination

P‐value

Hsieh 2002a

A/NC/20/99

39.8

50.1

50.1

631

P < 0.001

Hsieh 2002a

A/Pan/2007/99

31.6

125.9

50.1

158.5

P = 0.34

Hsieh 2002a

B/Yam/166/98

25.1

79.4

39.8

199.5

P = 0.105

Figuras y tablas -
Analysis 3.3

Comparison 3 Influenza immunity in vaccinated children with ALL receiving chemotherapy compared with vaccinated children with asthma, Outcome 3 Geometric mean titre (GMTs) pre‐ and post‐vaccination.

Study

Influenza strain

Vaccinated n%

Vaccinated Total N

Non‐vaccinated n%

Chisholm 2001

H1N1

14 (48%)

29

Not available

Chisholm 2001

H3N2

16 (70%)

23

Not available

Chisholm 2001

B

18 (64%)

28

Not available

Chisholm 2001

Figuras y tablas -
Analysis 4.1

Comparison 4 Influenza immunity in vaccinated compared with non‐vaccinated paediatric oncology participants, Outcome 1 Number of participants achieving protective titre post‐vaccination (> 40) after last immunisation.

Study

Influenza strain

GMT pre vacc

GMT post vacc

P‐value

Chisholm 2001

H1N1

12.6 (95%CI 8.6‐19.2)

60.4 (95% CI 32.4‐112.8)

< 0.0001

Chisholm 2001

H3N2

23.2 (95% CI 8.6‐16.7)

124.9 (95% CI 72‐216.0)

<0.0001

Chisholm 2001

B

12 (95% CI 8.6‐16.7)

48.0 (95% CI 30‐76.7)

<0.0001

Figuras y tablas -
Analysis 4.2

Comparison 4 Influenza immunity in vaccinated compared with non‐vaccinated paediatric oncology participants, Outcome 2 Geometric mean titre (GMTs) pre‐ and post‐vaccination.

Study

Influenza strain

Group 1. First dose n%

Total N of participants

Group 1. Sec dose n%

Total N of participants

Group 2. First dose n%

Total N of participants

Group 2. Sec dose n%

Total N of participants

P‐value

Hsieh 2002a

A/NC/20/99

6 (42.9%)

14

6 (42.9%)

14

5 (45,5%

11

5 (45.5%)

11

0.84 = NS comparing Group 1 Second dose to Group 2 Second dose

Hsieh 2002a

A/Pan/2007/99

4 (28.6%)

14

5 (35.7%)

14

0 (0%)

11

1 (9.1%)

11

0.12 = NS comparing Group 1 Second dose to Group 2 Second dose

Hsieh 2002a

B/Yam/166/98

7 (50%)

14

8 (57.1%)

14

8 (72.7%)

11

7 (63.6%)

11

0.84 = NS comparing Group 1 Second dose to Group 2 Second dose

Figuras y tablas -
Analysis 5.1

Comparison 5 Influenza immunity in two vaccination schedules in children with ALL receiving maintenance chemotherapy, Outcome 1 Number of participants with four‐fold rise in antibody titre 4 weeks after last immunisation.

Study

Influenza strain

Group 1. First dose n%

Total N

Group 1. Sec dose n%

Total N

Group 2. First dose n%

Total N

Group 2. Sec dose n%

Total N

P‐value

Hsieh 2002a

A/NC/20/99

5 (55.6%)

9

5 (55.6%)

9

3 (60%)

5

3 (60%)

5

0.79= NS comparing Group 1 second dose to Group 2 second dose

Hsieh 2002a

A/Pan/2007/99

2 (28.6%)

7

5 (71.4%)

7

0 (0%)

3

1 (33.3%)

3

0.35 = NS comparing Group 1 second dose to Group 2 second dose

Hsieh 2002a

B/Yam/166/98

6 (85.7%)

7

6 (85.7%)

7

5 (83.3%)

6

5 (83.3%)

6

0.73 = NS comparing Group 1 second dose to Group 2 second dose

Figuras y tablas -
Analysis 5.2

Comparison 5 Influenza immunity in two vaccination schedules in children with ALL receiving maintenance chemotherapy, Outcome 2 Number of participants achieving protective titre post‐vaccination (> 40) after immunisation.

Table 1. Cochrane Childhood Cancer Group guidelines on quality assessment of randomised controlled trials

Assessment of methodological quality of randomised controlled trials

Selection bias
Allocation concealment:
A. Adequate: use of randomisation method that did not allow investigator and participant to know or influence the allocation of treatment before eligible participants entered the study
B. Unclear: randomisation stated but no information on method used is available
C. Inadequate: use of alternate medical record numbers or unsealed envelopes as randomisation method, and/or information in the study indicates that investigators or participants could have influenced the allocation of treatment

Performance bias
Blinding of care providers: yes/no/unclear
Blinding of participants: yes/no/unclear
Care providers and participants are considered not blinded if the intervention group can be identified in > 20% of participants because of side effects of treatment

Detection bias
Blinding of outcome assessors: yes/no/unclear

Attrition bias
Intention‐to‐treat analysis:
A. Yes: all participants analysed in the treatment group to which they were allocated, regardless of whether or not they received the allocated intervention
B. No: some participants (< 5%, 5% to 10%, 10% to 20%, > 20%) not analysed in the treatment group to which they were randomly assigned because they did not receive the study intervention or they withdrew from the study, or because of a protocol violation
C. Unclear: inability to determine whether participants were analysed according to the intention‐to‐treat principle after contact with the authors

Completeness of follow‐up
Percentage of participants excluded or lost to follow‐up for the different treatment groups for primary and secondary outcomes (< 5%, 5% to 10%, 10% to 20%, > 20%)

Figuras y tablas -
Table 1. Cochrane Childhood Cancer Group guidelines on quality assessment of randomised controlled trials
Table 2. Newcastle‐Ottawa quality assessment scale

Scale

Cohort studies

Note: A study can be awarded a maximum of 1 star for each numbered item within the Selection and Outcome categories. A maximum of 2 stars can be given for Comparability. A total of 9 stars can be awarded.

Selection
1. Representativeness of the exposed cohort (1 star*)
a) Truly representative of the exposed cohort
b) Somewhat representative of the exposed cohort
c) Selected group of users, e.g. nurses, volunteers
d) No description of the derivation of the cohort

2. Selection of the non‐exposed cohort (1 star*)
a) Drawn from the same community as the exposed cohort
b) Drawn from a different source
c) No description of the derivation of the non‐exposed cohort

3. Ascertainment of exposure (1 star*)
a) Secure record
b) Structured interview
c) Written self‐report
d) No description

4. Demonstration that outcome of interest was not present at start of study (1 star*)
a) Yes
b) No

Comparability
1. Comparability of cohorts on the basis of the design or analysis (max 2 stars**)
a) Study controls for age
b) Study controls for time on chemotherapy

Outcome (1 star*)
1. Assessment of outcome
a) Independent blind assessment
b) Record linkage
c) Self‐report
d) No description

2. Was follow‐up long enough for outcomes to occur? (1 star*)
(1) Yes
(2) No

3. Adequacy of follow‐up of cohorts (1 star*)
a) Complete follow‐up ‐ all participants accounted for
b) Participants lost to follow‐up unlikely to introduce bias ‐ small number lost > 80% follow‐up
c) Follow‐up rate < 80% and no description of those lost
d) No statement

Figuras y tablas -
Table 2. Newcastle‐Ottawa quality assessment scale
Table 3. Quality of included CCTs

Selection

Comparability

Outcome

Total

Chisholm 2001

4 stars (classified A)

1 star

2 stars (poor follow‐up) classified as B

7 stars

Chisholm 2005

4 stars (classified A)

1 star

2 stars (poor follow‐up) classified as B

7 stars

Gross 1978

4 stars (classified A)

2 stars

3 stars

9 stars

Hsieh 2002a

4 stars (classified A)

2 stars

3 stars

9 stars

Lange 1979

4 stars (classified A)

2 stars

2 stars (poor follow‐up) classified as B

8 stars

Matsuzaki 2005

4 stars (classified A)

2 stars

3 stars

9 stars

Porter 2004

4 stars (classified A)

2 stars

2 stars (poor follow‐up) classified as B

8 stars

Shahgholi 2010

4 stars (classified A)

2 stars

2 stars (poor follow‐up of adverse events

classified as B)

8 stars

Steinherz 1980

4 stars (classified A)

1 star

2 stars (poor follow‐up) classified as B

7 stars

Figuras y tablas -
Table 3. Quality of included CCTs
Table 4. Quality of RCT

Scored items

Hsieh 2002

Randomisation performed

Yes, method not stated

Allocation concealment

Unclear

Blinding of care providers

Unclear

Blinding of participants

No

Blinding of outcome assessors

Yes

Intention‐to‐treat analysis

Yes

Completeness of follow‐up

None lost to follow‐up

Figuras y tablas -
Table 4. Quality of RCT
Comparison 1. Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated children not receiving chemotherapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants achieving protective titre post‐vaccination (> 32 or 40) after last immunisation Show forest plot

Other data

No numeric data

2 Number of participants with four‐fold rise in antibody titre after last immunisation Show forest plot

Other data

No numeric data

3 Geometric mean titre (GMTs) pre‐ and post‐vaccination Show forest plot

Other data

No numeric data

Figuras y tablas -
Comparison 1. Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated children not receiving chemotherapy
Comparison 2. Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated healthy children

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants with four‐fold rise in antibody titre after last immunisation Show forest plot

Other data

No numeric data

2 Geometric mean titre (GMTs) pre‐ and post‐vaccination Show forest plot

Other data

No numeric data

Figuras y tablas -
Comparison 2. Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated healthy children
Comparison 3. Influenza immunity in vaccinated children with ALL receiving chemotherapy compared with vaccinated children with asthma

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants with four‐fold rise in antibody titre 4 weeks after the last immunisation Show forest plot

Other data

No numeric data

2 Number of participants achieving protective titre post‐vaccination (> 40) after last immunisation Show forest plot

Other data

No numeric data

3 Geometric mean titre (GMTs) pre‐ and post‐vaccination Show forest plot

Other data

No numeric data

Figuras y tablas -
Comparison 3. Influenza immunity in vaccinated children with ALL receiving chemotherapy compared with vaccinated children with asthma
Comparison 4. Influenza immunity in vaccinated compared with non‐vaccinated paediatric oncology participants

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants achieving protective titre post‐vaccination (> 40) after last immunisation Show forest plot

Other data

No numeric data

2 Geometric mean titre (GMTs) pre‐ and post‐vaccination Show forest plot

Other data

No numeric data

Figuras y tablas -
Comparison 4. Influenza immunity in vaccinated compared with non‐vaccinated paediatric oncology participants
Comparison 5. Influenza immunity in two vaccination schedules in children with ALL receiving maintenance chemotherapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants with four‐fold rise in antibody titre 4 weeks after last immunisation Show forest plot

Other data

No numeric data

2 Number of participants achieving protective titre post‐vaccination (> 40) after immunisation Show forest plot

Other data

No numeric data

Figuras y tablas -
Comparison 5. Influenza immunity in two vaccination schedules in children with ALL receiving maintenance chemotherapy