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Influenza vaccination in children being treated with chemotherapy for cancer

  1. Ginette M Goossen1,
  2. Leontien CM Kremer2,
  3. Marianne D van de Wetering2,*

Editorial Group: Cochrane Childhood Cancer Group

Published Online: 1 AUG 2013

Assessed as up-to-date: 23 FEB 2013

DOI: 10.1002/14651858.CD006484.pub3


How to Cite

Goossen GM, Kremer LCM, van de Wetering MD. Influenza vaccination in children being treated with chemotherapy for cancer. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006484. DOI: 10.1002/14651858.CD006484.pub3.

Author Information

  1. 1

    Erasmus MC - Sophia Children's Hospital, Faculty of Medical Sciences, Rotterdam, Netherlands

  2. 2

    Emma Children's Hospital / Academic Medical Center, Department of Paediatric Oncology, Amsterdam, Netherlands

*Marianne D van de Wetering, Department of Paediatric Oncology, Emma Children's Hospital / Academic Medical Center, PO Box 22660 (room G8-235), Amsterdam, 1100 DD, Netherlands. m.d.vandewetering@amc.uva.nl.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 1 AUG 2013

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Characteristics of included studies [ordered by study ID]
Chisholm 2001

MethodsSingle-centre CCT conducted in the United Kingdom during the 1995-1996 and 1996-1997 influenza seasons

Serology of non-immunised paediatric oncology participants is compared with that of immunised paediatric oncology participants


Participants42 immunised and 42 non-immunised children with various malignancies. Most children were receiving chemotherapy, but participants who had completed chemotherapy within the past 6 months were also included. Children < 6 months of age were excluded; otherwise age was not specified


InterventionsTrivalent inactivated (split virion; Aventis Pasteur MSD) influenza vaccine subcutaneously, which contained the following strains in 1995: A/Taiwan/1/86, A/Johannesburg/34/94, B/Beijing/184/93. In 1996 A/Wahun/359/95 replaced the H3N2 component

Subjects received two doses of 0.5 ml for children > 4 years and 0.25 ml for children ≤ 4 years at 4-week intervals


Outcomes(1) Development of protective HI titre (≥ 40) post-vaccination
(2) Pre- and post-vaccination GMT
(3) Adverse reactions, although it is not specified how this outcome was measured

(1) and (3) only for immunised group


Notes(1) No follow-up serum was taken from 15/42 (36%) non-immunised children
(2) Children who had completed chemotherapy within the last 6 months were also immunised, contrary to the inclusion criteria for this review. However, in subgroup analysis, the difference in post-vaccination titre of those on chemotherapy compared with those off chemotherapy was not significant

Chisholm 2005

MethodsSingle-centre CCT conducted in the United Kingdom during the 2001-2002 and 2002-2003 influenza seasons


Participants59 children with various non-leukaemic malignancies who were receiving chemotherapy and 10 children with various non-leukaemic malignancies who had been off chemotherapy for 4 weeks to 6 months. Age between 6 months and 16 years


InterventionsTrivalent inactivated split virion (Aventis Pasteur MSD) subcutaneously, with the following strains in 2001-2002: A/New Cal/20/99 (H1N1), A/Panama/2007/99 (H3N2), B/Sichuan/379/99. In 2002-2003, B/Hong Kong/331/01 replaced B/Sichuan/379/99

Age-dependent schedule: < 4 years: two doses of 0.25 ml 3 to 4 weeks apart. 4 to 12 years: two doses of 0.5 ml 3 to 4 weeks apart. > 13 years: one dose of 0.5 ml. Previously immunised children: one dose 0.25 ml (< 4 years) or 0.5 ml (> 4 years)


Outcomes(1) Seroconversion (defined as four-fold rise in antibody titre) after vaccination
(2) Development of protective HI titre (≥ 32) post-vaccination
(3) Pre- and post-vaccination GMT
(4) Adverse reactions


NotesResults of children off chemotherapy stated only as "no impact" in subgroup analysis; no separate results were presented. Authors were contacted for additional information on the results of children off chemotherapy, and these results were obtained

Gross 1978

MethodsMulti-centre CCT conducted in New York, USA

Response to influenza vaccine in children with cancer who were receiving chemotherapy was compared with that of children with cancer off chemotherapy


Participants68 children with various malignancies who were receiving chemotherapy and 74 children with various malignancies who had been off chemotherapy for at least the last 1 month. Mean age 10 years (range 3 to 18 years)


InterventionsVarious influenza vaccines were used: (1) split-product vaccine (Parke-Davis) containing 400 CCA units of A/NJ/8/76 and 400 CCA of A/Vic/3/75 per dose, (2) whole virus vaccine (Merrell-National vaccine) containing 100 CCA units of A/NJ/8/76 and 100 CCA units of A/Vic/3/75, (3) whole virus vaccine (Merck Sharp & Dohme vaccine) containing 50 CCA units of A/NJ/8/76 and 50 CCA units of A/Vic/3/75

Subjects received two injections with a 1-month interval between doses. 3- to 5-year-olds received half the amount given to older children


Outcomes(1) Pre- and post-vaccination GMT
(2) Development of protective HI titre (≥ 40) post-vaccination
(3) Adverse reactions


Notes

Hsieh 2002a

MethodsRCT conducted in Taiwan during the 2000-2001 influenza season

Children with ALL were randomly assigned to one of two vaccination protocols


Participants25 children with ALL receiving maintenance chemotherapy. Mean age 7.3 years


InterventionsTrivalent inactivated split virus (Vaxigrip) influenza vaccine A/Panama/2007/99 (H3N2), A/New Caledonis/20/99 (H1N1), B/Yamanashi/166/98. Participants received two 0.5 ml doses containing 15 µg hemagglutinin, 4 weeks apart

Of the children with ALL, n = 14 received dose 1 of vaccine and reinduction chemotherapy on the same day; 4 weeks later, they received dose 2. N = 11 received dose 1 alone, 4 weeks later, they received dose 2 + reinduction chemotherapy on the same day


Outcomes(1) GMT pre- and post-vaccination
(2) Development of protective HI titre (≥ 40) post-vaccination
(3) Four-fold rise in antibody titre after vaccination
(4) Adverse reactions


NotesAdditional information on randomisation methods was requested and not obtained

Hsieh 2002b

MethodsCCT conducted in Taiwan during the 2000-2001 influenza season

Response to influenza vaccine in children with ALL is compared with that of children with asthma


Participants30 children with asthma in remission (no inhaled steroids within 2 weeks or oral steroids within 1 month before influenza vaccination), mean age 6.5 years, compared with 25 children with ALL receiving maintenance chemotherapy, mean age 7.3 years


InterventionsTrivalent inactivated split virus (Vaxigrip) influenza vaccine A/Panama/2007/99 (H3N2), A/New Caledonis/20/99 (H1N1), B/Yamanashi/166/98. Participants received two 0.5 ml doses containing 15 µg hemagglutinin, 4 weeks apart


Outcomes(1) GMT pre- and post-vaccination
(2) Development of protective HI titre (≥ 40) post-vaccination
(3) Four-fold rise in antibody titre after vaccination
(4) Adverse reactions


NotesDosage: > 8 years received 1 dose, and children younger than 8 received two doses of vaccine

Lange 1979

MethodsCCT conducted in the USA

Responses to influenza vaccine of children with ALL on maintenance chemotherapy were compared with those of healthy siblings and children with ALL off chemotherapy


Participants22 children with ALL in first remission on maintenance chemotherapy (mean age 9.8 years, range 5 to 15). Controls were 22 age-matched siblings (mean age 10.8 years, range 2 to 18) and 16 similarly matched children with ALL who were no longer receiving chemotherapy for 4 to 30 months (mean age 10.9 years, range 7 to 16)


InterventionsBivalent split-product influenza vaccine containing the following strains: A/Vic/75, A/NJ/76. Participants received two doses of 0.5 ml 4 weeks apart, with each dose containing 200 CCA of A/Vic/75 and A/NJ/76


Outcomes(1) Pre- and post-vaccination GMT
(2) Adverse reactions


NotesA discrepancy in the number of sibling controls was noted: 50 sibling controls were included according to the abstract and table 1, but 22 sibling controls are mentioned in the article under Materials and Methods

Matsuzaki 2005

MethodsCCT conducted in Japan during the 2003-2004 influenza season

Response to influenza vaccine in children with cancer who are receiving chemotherapy is compared with that of children with cancer off chemotherapy


Participants44 children with various types of malignancies, of whom 18 were receiving chemotherapy and 26 had finished chemotherapy for 1 to 60 months. Age 1 to 18 years


InterventionsTrivalent inactivated split (KAKETSUKEN) influenza vaccine subcutaneously, containing 30 µg HA per ml of each of the following strains: A/New Caledonia/20/99 (H1N1), A/Panama/2007/99, B/Shangdong/7/97. Participants received two doses, 2 to 4 weeks apart at doses of 0.2 ml for children aged 1 to < 6 years, 0.3 ml for those aged 6 to < 13 years and 0.5 ml for those 13 years of age or older, according to recommendations in Japan


Outcomes(1) Seroconversion (defined as four-fold rise in antibody titre) after two vaccinations
(2) Achieving protective antibody titre (HI antibody titre ≥ 40) after two vaccinations
(3) Adverse effects


NotesNo numbers pertaining to adverse effects stated

Porter 2004

MethodsSingle-centre CCT conducted in Nashville, USA, during the 2001-2002 influenza season

Responses of children with ALL to influenza vaccine were compared with those of healthy children


Participants20 children with ALL in first remission receiving maintenance chemotherapy, who had completed their last delayed intensification at least 4 weeks earlier. Mean age 7.7 years. 49 healthy children (14 healthy siblings and 35 additional healthy children in the community) were enrolled as controls, mean age 9.2 years


InterventionsTrivalent inactivated (Fluzone) influenza vaccine, containing the following strains: A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), B/Victoria/504/2000. According to ACIP guidelines, children 9 years of age or older and those previously immunised with influenza vaccine received one dose (0.5 ml), and children aged < 9 years and previously non-immunised children received two doses (each 0.5 ml), 1 month apart


Outcomes(1) Pre- and post-vaccination GMT
(2) Seroconversion (defined as four-fold rise in antibody titre) after the last vaccination
(3) Adverse reactions after vaccination


NotesData on 3/49 healthy children were not included because they did not provide post-vaccination serology

In this study it was not stated what HI titre was considered protective, nor what percentage of participants reached a protective HI titre

Shahgholi 2010

MethodsSingle-centre controlled clinical trial conducted in Iran during the 2007-2008 influenza season. Responses of children with ALL on maintenance therapy to influenza vaccine were compared with those of healthy siblings


Participants32 children aged 1 to 18 years with ALL in first remission on maintenance chemotherapy. Controls were 30 healthy siblings, similar in age and gender distribution

Previously vaccinated children were excluded from the study


InterventionsTrivalent inactivated influenza vaccine (Influvac), containing the following strains: A/Solomon Islands 3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), B/Malaysia/2506/2004. Participants received two doses of 0.25 ml 3 to 4 weeks apart for children < 36 months of age, two doses of 0.5 ml for children 36 months to 13 years and one dose of 0.5 ml  for children aged > 13 years


Outcomes(1) Development of protective HI titre (> 40) post-vaccination; this is considered seroconversion (defined as four-fold rise in antibody titre) after vaccination

(3) Pre- and post-vaccination GMT

(4) Adverse reactions


NotesData on adverse reactions were available for 35 of 62 participants (56%)

Steinherz 1980

MethodsSingle-centre CCT conducted in New York, USA, during the 1976-1977 influenza season

Responses to influenza vaccine of children with cancer who are receiving chemotherapy were compared with those of healthy siblings and children with cancer off chemotherapy


Participants160 children, of whom 147 children had various types of malignancies (median age 11.6 years) and 13 siblings served as normal controls (median age 8.6 years). Of the 147 children with cancer, 106 were receiving chemotherapy and 41 had been off chemotherapy for 30 or more days


InterventionsBivalent split-product influenza A vaccine intramuscularly, containing the following strains: A/New Jersey/8/76 (Hsw1N1), A/Victoria/3/75 (H3N2). Two doses of 0.5 ml, each containing 200 CCA units, were administered 4 weeks apart


Outcomes(1) Significant antibody response (defined as four-fold rise in HI titre) four to six weeks after two immunisations
(2) Achieving protective HI antibody titre (defined as ≥ 32) 4 to 6 weeks after two immunisations
(3) Adverse reactions after vaccination


NotesThe National Influenza Immunization Program ended in December 1976. By that time, only 50/106 participants receiving chemotherapy and 21/41 participants off chemotherapy had received both immunisations. The age and sex distributions remained similar to those of the original group of 160 participants. Age and sex distributions of the healthy sibling controls are not mentioned

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Adell 2002(1) Participant population consisted mainly of adults
(2) No outcomes relevant to this review were assessed
(3) Participants who did not receive chemotherapy in the month before vaccination were included in the chemotherapy group

Ahmed 1996Review on efficacy of influenza vaccine

Allison 1977Details pertaining to chemotherapy were not adequately specified; therefore, not clear whether participants who received vaccine were receiving chemotherapy or had received chemotherapy during the month before vaccination. Not clear how treatment group was defined

Arola 1995No vaccines administered

Barnes 2001Review on infections after bone marrow transplantation

Bektas 2007Lack of a control group

Borella 1971Not clear how outcome of influenza-like illness was assessed; not specified by whom symptoms of influenza-like illness were scored and how many symptoms were necessary for diagnosis of influenza-like illness; therefore many viral illnesses were included. Impossible to specify the treatment and control groups

Brown 1982(1) Presented as summary; insufficient information provided on characteristics of participants and controls
(2) Control group data were obtained from another trial

Brown 1983Review on influenza and pneumococcal vaccination in cancer patients

Brunell 1977(1) Insufficient information provided on methodology, characteristics of participants and controls
(2) Results are not presented

Brydak 199742/49 participants had already finished chemotherapy treatment (6 months to 3 years)

Brydak 1998Only 2 subjects were receiving chemotherapy at time of study

Engelhard 1993(1) Lack of a control group
(2) Participants did not receive chemotherapy or radiotherapy in the month before vaccination
(3) Adults included in study population, results of children not presented separately

Esposito 2009Commentary on influenza vaccination in children with cancer receiving chemotherapy

Feery 1979Control group data were obtained from another trial

Ganz 1978Adult study population

Gribabis 1994Adult study population

Gross 1985Review of influenza vaccine in cancer patients receiving chemotherapy

Hayden 2000Review on treatment and prophylaxis of influenza

Hicks 2003Review on various viral infections in cancer patients

Jackowska 1996Same patient population as in Brydak 1997

Kandel 2005Review on prevention and treatment of influenza

Kempe 1989Participants were not vaccinated

Louie 2006Only 3 children with leukaemia/blood dyscrasia in study population; not stated whether they were vaccinated

Mayr 1974Adult study population

McIntosh 2003Review on vaccines for children

Modlin 1977Children with malignancies were not included in the study

Morris 1990Review on viral infections in children with cancer

Pauksen 2000Adult study population

Reilly 2010Lack of a control group

Ridgway 1993Review on eight vaccines (including influenza vaccine) in children with cancer

Schafer 1979(1) Adult study population
(2) Not clear whether participants received chemotherapy in the month before vaccination

Smithson 1978Control group data were obtained from another trial

Somani 1995Review on re-immunisation with various vaccines after bone marrow transplantation

Stiver 1978Adult study population

Sumaya 1977Control group data were obtained from other trials

Sumaya 1982Lack of a control group

Uchaikin 1999Participants did not receive chemotherapy in the month before vaccination

Yamada 19826/8 participants had already finished chemotherapy

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

StudyInfluenza strainOn chemotherapy n%On chemotherapy Total NOff chemotherapy n%Off chemotherapy Total NP-value

Chisholm 2005A/NC/20/9916 (42%)383 (43%)71.00

Chisholm 2005A/PAN/2007/9912 (50%)242 (40%)50.70

Chisholm 2005B/Sichuan 379 9926 (49%)533 (33%)90.48

Gross 1978A/NJ/7620 (29%)6863 (85%)74< 0.001

Gross 1978A/Vic/7533 (49%)6865 (88%)74< 0.01

Gross 1978

Matsuzaki 2005A/NC/20/995 (42%)1218 (90%)200.006

Matsuzaki 2005A/PAN/2007/992 (25%)810 (83%)120.019

Matsuzaki 2005B/Sha/7/975 (29%)1711 (44%)250.518

Steinherz 1980A/NJ/7613 (26%)5012 (57%)21< 0.05

Steinherz 1980A/Vic/7531 (61%)5016 (75%)210.380

Steinherz 1980

 
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.
Number of participants with four-fold rise in antibody titre after last immunisation

StudyInfluenza strainOn chemotherapy n%On chemotherapy Total NOff chemotherapy n%Off chemotherapy Total NP-value

Chisholm 2005A/NC/20/9930 (53%)564 (44%)90.13

Chisholm 2005A/PAN/2007/9919 (34%)563 (33%')90.85

Chisholm 2005B/Sichuan 379 9928 (50%)565 (55%)90.86

Matsuzaki 2005A/NC/20/996 (38%)1620 (83%)240.004

Matsuzaki 2005A/PAN/2007/994 (25%)1612 (50%)240.105

Matsuzaki 2005B/Shan/7/976 (33%)1814 (54%)260.227

Steinherz 1980A/NJ/7619 (38%)5016 (76%)21< 0.01

Steinherz 1980A/Vic/7526 (52%)5018 (86%)21< 0.05

Steinherz 1980

 
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.
Geometric mean titre (GMTs) pre- and post-vaccination

StudyInfluenza strainOn chemotherapy GMT pre-vaccinationOn chemotherapy GMT post-vaccinationOff chemotherapy GMT pre-vaccinationOff chemotherapy GMT post-vaccinationP-value

Chisholm 2005A/NC/20/99< 8-16290< 8-162841.00

Chisholm 2005A/PAN/2007/99< 8-1687.2< 8-161480.30

Chisholm 2005B/Sichuan 379 99<865.3<8720.84

Gross 1978A/NJ/76014584*< 0.001

Gross 1978A/Vic/75112317133*< 0.01

Gross 1978

Lange 1979A/NJ/76< 837.74 ± 1.28< 8176.88 ±1.14< 0.01

Lange 1979A/Vic/7510.62 ± 1.1461.92 ±1.2612.88 ± 1.15203,19 ±1.26< 0.01

Lange 1979

 
Comparison 2. Influenza immunity in vaccinated children receiving chemotherapy compared with vaccinated healthy children

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants with four-fold rise in antibody titre after last immunisationOther dataNo numeric data

 2 Geometric mean titre (GMTs) pre- and post-vaccinationOther dataNo numeric data

 
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.
Number of participants with four-fold rise in antibody titre after last immunisation

StudyInfluenza strainOn chemotherapy n%On chemotherapy

Total N
Healthy n%Healthy

Total N
P-value

Porter 2004A/NC/20/9913 (65%)2041 (89%)46P = 0.034

Porter 2004A/PAN/2007/9913 (65%)2036 (78%)46P = 0.258

Porter 2004B/Vic/504/200012 (60%)2035 (76%)46P = 0.185

Shahgholi 2010A/SI 3/200618 (56,2%)3224 (80%)30P = 0.04

Shahgholi 2010A/Wis/67/200513 (40,6%)3216 (53,3%)30P = 0.31

Shahgholi 2010B/Mal/2506/200419 (59,4%)3225 (83,3%)30P = 0.038

Steinherz 1980A/NJ/7619 (38%)505 (71%)7P = 0.204

Steinherz 1980A/Vic/7526 (52%)506 (86%)7P = 0.202

Steinherz 1980

 
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.
Geometric mean titre (GMTs) pre- and post-vaccination

StudyInfluenza strainOn chemotherapy GMT pre-vaccinationOn chemotherapy GMT post-vaccinationHealthy GMT pre-vaccinationHealthy GMT post-vaccinationP-value

Lange 1979A/NJ/76<8 ± 0.0037.74 ± 1.28<8 ± 0.0052.39 ± 1.130.53

Lange 1979A/Vic/7510.62 ± 1.1461.92 ±1.2612.51 ±1.1270.34 ± 1.120.80

Lange 1979

Porter 2004A/NC/20/996.5053.8215.06367.03< 0.001

Porter 2004A/Pan/2007/9929.86152.2272.20577.59< 0.03

Porter 2004B/Vic/504/20008.5739.413.15165.37< 0.003

Shahgholi 2010A/SI 3/200632,552,8731,576,380,13

Shahgholi 2010A/Wis/67/20055481,8754145,410.04

Shahgholi 2010B/Mal/2506/200412,825,411738.070.10

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

StudyInfluenza strainALL on chemotherapy n%ALL on chemotherapy

Total N
Asthma n%Asthma

Total N
P-value

Hsieh 2002aA/NC/20/996 (24%)2523 (77%)30P < 0.0001

Hsieh 2002aA/Pan/2007/9915 (60%)2519 (63%)30P = 0.980
NS

Hsieh 2002aB/Yam/166/9811 (44%)2520 (67%)30P = 0.157

 
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.
Number of participants achieving protective titre post-vaccination (> 40) after last immunisation

StudyInfluenza strainALL on chemotherapy n%ALL group

Total N
Asthma %nAsthma

Total N
P-value

Hsieh 2002aA/NC/20/996 (60%)109 (90%)10P = 0.302

Hsieh 2002aA/PAN/2007/9911 (85%)138 (73%)11P = 0.834

Hsieh 2002aB/Yam/166/988 (57%)1410 (83%)12P = 0.309

 
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.
Geometric mean titre (GMTs) pre- and post-vaccination

StudyInfluenza strainALL GMT pre-vaccinationALL GMT post-vaccinationAsthma GMT pre-vaccinationAsthma GMT post-vaccinationP-value

Hsieh 2002aA/NC/20/9939.850.150.1631P < 0.001

Hsieh 2002aA/Pan/2007/9931.6125.950.1158.5P = 0.34

Hsieh 2002aB/Yam/166/9825.179.439.8199.5P = 0.105

 
Comparison 4. Influenza immunity in vaccinated compared with non-vaccinated paediatric oncology participants

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants achieving protective titre post-vaccination (> 40) after last immunisationOther dataNo numeric data

 2 Geometric mean titre (GMTs) pre- and post-vaccinationOther dataNo numeric data

 
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.
Number of participants achieving protective titre post-vaccination (> 40) after last immunisation

StudyInfluenza strainVaccinated n%Vaccinated Total NNon-vaccinated n%

Chisholm 2001H1N114 (48%)29Not available

Chisholm 2001H3N216 (70%)23Not available

Chisholm 2001B18 (64%)28Not available

Chisholm 2001

 
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.
Geometric mean titre (GMTs) pre- and post-vaccination

StudyInfluenza strainGMT pre vaccGMT post vaccP-value

Chisholm 2001H1N112.6 (95%CI 8.6-19.2)60.4 (95% CI 32.4-112.8)< 0.0001

Chisholm 2001H3N223.2 (95% CI 8.6-16.7)124.9 (95% CI 72-216.0)<0.0001

Chisholm 2001B12 (95% CI 8.6-16.7)48.0 (95% CI 30-76.7)<0.0001

 
Comparison 5. Influenza immunity in two vaccination schedules in children with ALL receiving maintenance chemotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants with four-fold rise in antibody titre 4 weeks after last immunisationOther dataNo numeric data

 2 Number of participants achieving protective titre post-vaccination (> 40) after immunisationOther dataNo numeric data

 
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.
Number of participants with four-fold rise in antibody titre 4 weeks after last immunisation

StudyInfluenza strainGroup 1. First dose n%Total N of participantsGroup 1. Sec dose n%Total N of participantsGroup 2. First dose n%Total N of participantsGroup 2. Sec dose n%Total N of participantsP-value

Hsieh 2002aA/NC/20/996 (42.9%)146 (42.9%)145 (45,5%115 (45.5%)110.84 = NS comparing Group 1 Second dose to Group 2 Second dose

Hsieh 2002aA/Pan/2007/994 (28.6%)145 (35.7%)140 (0%)111 (9.1%)110.12 = NS comparing Group 1 Second dose to Group 2 Second dose

Hsieh 2002aB/Yam/166/987 (50%)148 (57.1%)148 (72.7%)117 (63.6%)110.84 = NS comparing Group 1 Second dose to Group 2 Second dose

 
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.
Number of participants achieving protective titre post-vaccination (> 40) after immunisation

StudyInfluenza strainGroup 1. First dose n%Total NGroup 1. Sec dose n%Total NGroup 2. First dose n%Total NGroup 2. Sec dose n%Total NP-value

Hsieh 2002aA/NC/20/995 (55.6%)95 (55.6%)93 (60%)53 (60%)50.79= NS comparing Group 1 second dose to Group 2 second dose

Hsieh 2002aA/Pan/2007/992 (28.6%)75 (71.4%)70 (0%)31 (33.3%)30.35 = NS comparing Group 1 second dose to Group 2 second dose

Hsieh 2002aB/Yam/166/986 (85.7%)76 (85.7%)75 (83.3%)65 (83.3%)60.73 = NS comparing Group 1 second dose to Group 2 second dose

 
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%)

 
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

 
Table 3. Quality of included CCTs

SelectionComparabilityOutcomeTotal

Chisholm 20014 stars (classified A)1 star2 stars (poor follow-up) classified as B7 stars

Chisholm 20054 stars (classified A)1 star2 stars (poor follow-up) classified as B7 stars

Gross 19784 stars (classified A)2 stars3 stars9 stars

Hsieh 2002a4 stars (classified A)2 stars3 stars9 stars

Lange 19794 stars (classified A)2 stars2 stars (poor follow-up) classified as B8 stars

Matsuzaki 20054 stars (classified A)2 stars3 stars9 stars

Porter 20044 stars (classified A)2 stars2 stars (poor follow-up) classified as B8 stars

Shahgholi 20104 stars (classified A)2 stars2 stars (poor follow-up of adverse events

classified as B)
8 stars

Steinherz 19804 stars (classified A)1 star2 stars (poor follow-up) classified as B7 stars

 
Table 4. Quality of RCT

Scored itemsHsieh 2002

Randomisation performedYes, method not stated

Allocation concealmentUnclear

Blinding of care providersUnclear

Blinding of participantsNo

Blinding of outcome assessorsYes

Intention-to-treat analysisYes

Completeness of follow-upNone lost to follow-up