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Influenza vaccines in immunosuppressed adults with cancer

  1. Noa Eliakim-Raz1,*,
  2. Inbal Vinograd2,
  3. Anca Zalmanovici Trestioreanu3,
  4. Leonard Leibovici1,
  5. Mical Paul4

Editorial Group: Cochrane Gynaecological Cancer Group

Published Online: 29 OCT 2013

Assessed as up-to-date: 20 AUG 2013

DOI: 10.1002/14651858.CD008983.pub2


How to Cite

Eliakim-Raz N, Vinograd I, Zalmanovici Trestioreanu A, Leibovici L, Paul M. Influenza vaccines in immunosuppressed adults with cancer. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD008983. DOI: 10.1002/14651858.CD008983.pub2.

Author Information

  1. 1

    Beilinson Hospital, Rabin Medical Center, Department of Medicine E, Petah Tikva, Israel

  2. 2

    Schneider Children's Medical Centre of Israel, Pharmacy, Petah-Tikva, Israel

  3. 3

    Beilinson Campus, Rabin Medical Center, Department of Family Medicine, Petah Tikva, Israel

  4. 4

    Rambam Health Care Campus and the Technion-Israel Institute of Technology, Division of Infectious Diseases, Haifa, Israel

*Noa Eliakim-Raz, Department of Medicine E, Beilinson Hospital, Rabin Medical Center, 39 Jabotinski Street, Petah Tikva, 49100, Israel. noaeliakim@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 29 OCT 2013

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Characteristics of included studies [ordered by study ID]
Earle 2003

MethodsRetrospective, observational
Location and setting:USA, Boston


ParticipantsStage 4 colorectal adenocarcinoma, with active chemotherapy treatment

1225 adults, 1577 person-years: 626 person-years vaccinated, 951 person-years unvaccinated

mean age 74 year in both groups


InterventionsYearly influenza vaccination, examined through medical bills


Outcomes
  1. adjusted all cause mortality
  2. confirmed influenza
  3. pneumonia
  4. hospitalization duration
  5. chemotherapy interruptions
  6. influenza related mortality
  7. mean number of hospital days


NotesResults given per person-years


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-random

Allocation concealment (selection bias)High riskNon-random

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients follow-up

Selective reporting (reporting bias)Unclear risknone identified

Blinding of participants and personnel (performance bias)
All outcomes
High riskNon-blinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskNon-blinded

Machado 2005

MethodsRetrospective case-control (confirmed influenza versusno influenza)
Location and setting: Brazil


ParticipantsBMT recipients (CML, acute leukemia, severe aplastic anemia, NHL, MM, other)

43 participants eligible to receive influenza vaccination: 19 vaccinated 24 unvaccinated

mean age not reported


InterventionsInfluenza vaccination, obtained from review of participants' charts


Outcomes
  1. Confirmed influenza by direct immunofluorescence assay
  2. Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-random

Allocation concealment (selection bias)High riskNon-random

Incomplete outcome data (attrition bias)
All outcomes
High riskMortality - no record

Selective reporting (reporting bias)High riskThe only outcome reported was documented influenza

Blinding of participants and personnel (performance bias)
All outcomes
High riskNon-blinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskNon-blinded

Musto 1997

MethodsRandomized trial, open-label

Location and setting:Italy


ParticipantsMultiple myeloma, with active chemotherapy treatment

50 adults: 25 vaccinated 25 unvaccinated

mean age not reported


InterventionsInfluenza vaccination versus no vaccination, assigned by randomization


Outcomes
  1. Upper respiratory illnesses
  2. Pneumonia requiring hospitalisation
  3. Any hospitalization
  4. Influenza related mortality
  5. Local adverse events
  6. Mean duration of Influenza-like illness
  7. Non-programmed visits in haemato day hospital


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Selective reporting (reporting bias)Unclear riskMortality reported only due to influenza pneumonia

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo placebo used

Blinding of outcome assessment (detection bias)
All outcomes
High riskNone

Vinograd 2013

MethodsProspective observational
Location and setting: Israel


ParticipantsSolid malignancies, with active chemotherapy and haematological patients with active disease

806 adults: 387 vaccinated versus 419 unvaccinated

mean age 66 years in vaccinated group versus 60 years in unvaccinated


InterventionsPatients were followed up through medical personal hard copy files and through electronic patients’ health records, including inpatient and outpatient records. Telephone or personal interviews were also conducted to collect data on clinical outcomes and assure vaccination status.


Outcomes1. A composite of hospitalizations for fever or acute respiratory infection; and/or pneumonia necessitating antibiotic treatment; and/or chemotherapy interruptionsr elated to an infectious condition.

2. All cause mortality

3. Influenza-like illness

4. Laboratory confirmed influenza

5. Individual components of the primary outcome

6. Any hospitalization and hospitalizations days

7. Antibiotic treatment necessity in hospitalization

8. All delays in planned chemotherapy courses


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-random

Allocation concealment (selection bias)High riskNon-random

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Blinding of participants and personnel (performance bias)
All outcomes
High risk

Blinding of outcome assessment (detection bias)
All outcomes
High risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Adell 2002All participants vaccinated

Anderson 1999All participants vaccinated

Avetisyan 2008All participants vaccinated

Bedognetti 2009Lymphoma participants compared to healthy participants

Bedognetti 2010Lymphoma participants compared to healthy participants

Brydak 1999All participants vaccinated

Brydak 2001Healthy participants not vaccinated compared to breast cancer participants vaccinated

Brydak 2006Lymphoma participants compared to healthy participants

Buccalosi 1995All participants vaccinated

Lymphoma participants compared to healthy participants

Centkowski 2007All participants vaccinated

Lymphoma participants compared to healthy participants

Chadha 2009All participants vaccinated

De Lavallade 2011Comparison to healthy participants

Engelhard 1993All participants vaccinated

Comparing different doses of influenza vaccine

Feery 1977Comparison to healthy participants

Ganz 1978Comparison to healthy participants

Gribabis 1994All participants vaccinated

Hodges 1979Comparison to healthy participants

Issa 2011All participants vaccinated

Jo 2009Comparing different doses of influenza vaccine

Lachenal 2010Vaccination rate in haematological participants

Lankes 2009Association between influenza vaccination and risk of developing Non-Hodgkin lymphoma

Ljungman 2005Comparing different doses of influenza vaccine

Lo 1993Comparing different doses of influenza vaccine

Mazza 2005All participants vaccinated

Lymphoma participants compared to healthy participants

Mulder 2009All participants vaccinated

Comparison to healthy participants

Nordoy 2002All participants vaccinated

Ortbals 1977All participants vaccinated

Puthillath 2011All participants vaccinated

Serological outcomes only

Rapezzi 2003All participants vaccinated

Lymphoma participants compared to healthy participants

Robertson 2000Myeloma participants vaccinated compared to healthy participants' serum

Safdar 2006Comparing different influenza vaccines in Non-Hodgkin lymphoma patients

Schafer 1979All participants vaccinated

Haematological participants compared to healthy participants

Shildt 1979All participants vaccinated

Spies 2008No information about control group vaccination prior to study.

Mortality is reported in a two-year follow-up, while we stated maximal follow-up period until end of the influenza season following vaccination

Spitaleri 2010All participants vaccinated

Stiver 1978All participants vaccinated

Takata 2009All participants vaccinated

Van der Velden 2001All participants vaccinated

Xu 2009All participants vaccinated

Comparison to healthy participants

Yalc 2010All participants vaccinated

 
Comparison 1. Influenza vaccine versus none

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

 1 All-cause mortality2Odds Ratio (Fixed, 95% CI)Totals not selected

    1.1 Non-randomised, adjusted, events/person-years
1Odds Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Non-randomised, adjusted, events/person
1Odds Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Influenza-like illness2Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 Randomised, events/person
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Non-randomised, unadjusted, events/person
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Confirmed influenza3Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 Non-randomised, unadjusted, events/person-years
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Non-randomised, unadjusted, events/persons with ILI
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 Non-randomised, unadjusted, events/persons
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Pneumonia3Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    4.1 Randomised, events/person
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 Non-randomised, unadjusted, events/person-years
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 Non-randomised, unadjusted, events/person
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Any hospitalization2Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    5.1 Randomised, events/person
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 Non-randomised, unadjusted, events/person
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison. influenza vaccination for prevention of influenza among adults with cancer

influenza vaccination for prevention of influenza among adultswith cancer

Patient or population: patients with prevention of influenza among adults with cancer
Settings:
Intervention: influenza vaccination

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlInfluenza vaccination

All-cause mortality
Follow-up: 4-12 months
Study populationOR 0.88
(0.78 to 1)
1577
(1 study)
⊕⊝⊝⊝
very low1,2
Earle 2003

397 per 1000367 per 1000
(340 to 397)

Moderate

0 per 10000 per 1000
(0 to 0)

All-cause mortality
Follow-up: 5-7 months
Study populationOR 0.42
(0.24 to 0.75)
806
(1 study)
⊕⊝⊝⊝
very low1,3,4
Vinograd 2013

191 per 100090 per 1000
(54 to 150)

Moderate

0 per 10000 per 1000
(0 to 0)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Observational study, adjusted results reported but confounding cannot be ruled out
2 95% confidence interval up to 1
3 Broad 95% confidence intervals
4 58% reduction in the odds for death in the adjusted analysis
 
Table 1. Influenza frequency and related outcomes in HSCT recipients and adults with cancer

Ref.Type of malignancy (influenza years)No of casesInfluenza casesOutcome

Ljungman 2001allogeneic BMT/HSCT recipients (1997 to 1998)8191.7%Deaths 29%

autologous BMT/HSCT recipients (1997 to 1998)11540.2%Deaths 0%

allogeneic BMT/HSCT recipients (1997 to 2000)>819 Deaths 23%

autologous BMT/HSCT recipients (1997 to 2000)>1154 Deaths 22%

Hassan 2003allogeneic BMT/HSCT recipients (1996 to 2001)2302.2%Deaths 20%

autologous BMT/HSCT recipients (1996 to 2001)3960% 

Nichols 2004HSCT  recipients (within 120 days  after transplantation) (1989 to 2002)47971.3%Deaths 10%

Pneumonia 29%

Machado 2003HSCT recipients (URTI symptoms present) (2001 to 2002)17923%Deaths 0%

Chemaly 2006HSCT  recipients AND hematologic malignancies (retrospective study of patients with laboratory confirmed viral respiratory infection) (2000 to 2002)34333%Deaths 4%

Pneumonia 30%

HSCT recipients23029% 

Leukaemia6133% 

Lymphoma3751% 

Multiple myeloma1540% 

Yousuf 1997CLL /acute leukaemia (hospitalized patients) (1993 to 1994)4533%Deaths 27%

Pneumonia 80%

Elting 1995CLL /acute leukaemia (1991 to 1992)3711%Deaths 25%

Pneumonia 75%

Redelman-Sidi 2010solid cancers (H1N1 2009 pandemic)2267%0% Deaths

hematologic malignancies (H1N1 2009 pandemic)167 (96 HSCT)17% (22%)0% Deaths

 
Table 2. Newcastle-Ottawa Grading

SelectionComparabilityOutcometotal stars score





Representativeness of the exposed cohortSelection of the non exposed cohortAscertainment of exposureDemonstration that outcome of interest was not present at start of studyComparability * Assessment of outcomeWas follow-up long enough for outcomes to occurAdequacy of follow up of cohorts **

Earle 2003caaaNod ***aa5

Machado 2005caaaNobaa6

Vinograd 2013baa+baa+bb+caa10

 * The most important factor to control for was the cancer stage. The second most important factor was functional capacity
** A follow-up rate of >=80% was considered adequate
*** Procedure was described but considered inadequate (through billing accounts and other administrative databases)
 
Table 3. Summary of Main Outcomes

OutcomeDesignall-cause mortalityinfluenza-like- illnessinfluenza- related mortalityconfirmed influenzapneumoniaany hospitalizationchemotherapy interruptions









Vaccination statusYesNoYesNoYesNoYesNoYesNoYesNo

Earle 2003Retrospective observationalCox adjusted HR 0.88 (95% CI 0.77 to 0.99), 626 versus 951 py *0/626 py2/951 py0/626 py3/951 py7/626 py *33/951 py *mean days 15.6, 95% CI 13.3 to 17.8 (N = 626 py)mean days 16.4, 95% CI 14.3 to 18.4 (N = 951 py)mean 5.06 days (N = 626 py) **mean 6.04 days (N = 951 py) **

Machado 2005Retrospective case control2/19 *12/24 *

Musto 1997Randomized, open label8/25 *18/25 *0/252/250/254/252/25 *12/25 *

Vinograd 2013Prospective observationalMV adjusted OR 0.43 (95% CI 0.26 to 0.71) (387 versus 419p); MV adjusted OR in propensity-matched cohort 0.42 (95% CI 0.76 to 0.24) (218p versus 218p)134/387137/4192/3874/41981/38778/419183/387205/41997/387116/419

 py= persons years
* denoted statistically significant difference, P < 0.05
** mean interval between chemotherapy bills