Influenza vaccines in immunosuppressed adults with cancer

Roni Bitterman; Noa Eliakim‐Raz; Inbal Vinograd; Anca Zalmanovici Trestioreanu; Leonard Leibovici; Mical Paul

doi:10.1002/14651858.CD008983.pub3

Vacunas contra la gripe en adultos con cáncer e inmunodeprimidos

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References

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included studies
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References to other published versions of this review

Jump to:

included studies
excluded studies
additional references

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. [DOI: 10.1002/14651858.CD008983.pub2]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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excluded studies

Ambati 2015

Methods	Randomised controlled study Location: Brazil
Participants	Patients more than 7 days before allogeneic HSCT 78 patients, of which 19 children. 40 were vaccinated and 38 were unvaccinated Mean age not reported
Interventions	Influenza vaccination versus no vaccination, assigned by randomisation
Outcomes	1. All‐cause mortality 2. Influenza‐related mortality 3. Vaccine immunogenicity reported as seroconversion rate or geometric mean titres 4. Laboratory‐confirmed influenza infections
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	List of random numbers with their respective randomisation group was generated by a website
Allocation concealment (selection bias)	Low risk	Opaque envelopes sequentially numbered and sealed
Incomplete outcome data (attrition bias) All outcomes	Low risk	No patients lost to follow up for the mortality outcome.
Selective reporting (reporting bias)	High risk	No primary endpoint defined in methods, no registry. Seroconversion reported at multiple time points
Other bias	Low risk	No baseline imbalances, sponsored by academic grant, no sample size calculation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	No blinding, but outcomes are objective
Blinding of outcome assessment (detection bias) All outcomes	Low risk	No blinding, but outcomes are objective

Earle 2003

Methods	Retrospective, observational cohort study Location: USA, Boston
Participants	Stage 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
Interventions	Yearly influenza vaccination, examined through medical bills
Outcomes	Adjusted all‐cause mortality Confirmed influenza Pneumonia Hospitalisation duration Chemotherapy interruptions Influenza‐related mortality Mean number of hospital days
Notes	Results given per person‐years
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Non‐random
Allocation concealment (selection bias)	High risk	Non‐random
Incomplete outcome data (attrition bias) All outcomes	High risk	Mortality data were given only for 697 of 1054 patients.
Selective reporting (reporting bias)	Low risk	None identified
Other bias	High risk	No control for cancer stage and functional capacity, no sample size calculation, funding not mentioned.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Non‐blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Non‐blinded

Machado 2005

Methods	Retrospective case‐control study (confirmed influenza versus no influenza) Location and setting: Brazil
Participants	HSCT recipients (CML, acute leukaemia, severe aplastic anaemia, NHL, MM, other) 43 participants eligible to receive influenza vaccination: 19 vaccinated 24 unvaccinated Mean age not reported
Interventions	Influenza vaccination, obtained from review of participants' charts
Outcomes	Confirmed influenza by direct immunofluorescence assay Adverse events
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Non‐random
Allocation concealment (selection bias)	High risk	Non‐random
Incomplete outcome data (attrition bias) All outcomes	High risk	Mortality ‐ no record
Selective reporting (reporting bias)	High risk	The only outcome reported was documented influenza
Other bias	High risk	No control for cancer stage and functional capacity, funding not mentioned, no sample size calculation
Blinding of participants and personnel (performance bias) All outcomes	High risk	Non‐blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Non‐blinded

Musto 1997

Methods	Randomised trial, open‐label Location: Italy
Participants	MM, with active chemotherapy treatment 50 adults: 25 vaccinated 25 unvaccinated Mean age not reported
Interventions	Influenza vaccination versus no vaccination, assigned by randomisation
Outcomes	Upper respiratory illnesses Pneumonia requiring hospitalisation Any hospitalisation Influenza‐related mortality Local adverse events Mean duration of Influenza‐like illness Non‐programmed visits in haematology day hospital
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	No patients lost to follow up
Selective reporting (reporting bias)	Unclear risk	Mortality reported only due to influenza pneumonia
Other bias	Unclear risk	No reported baseline imbalances, funding not mentioned, no sample size calculation
Blinding of participants and personnel (performance bias) All outcomes	High risk	No placebo used
Blinding of outcome assessment (detection bias) All outcomes	High risk	None

Natori 2017

Methods	Randomised controlled trial Location: Canada, Toronto
Participants	At least 12 weeks post HSCT 73 adults: 35 received adjuvanted vaccine and 38 received non‐adjuvanted vaccine Median age 54.5 years in adjuvanted vaccine group versus 52.5 years in non‐adjuvanted vaccine group
Interventions	Adjuvanted influenza vaccination versus non‐adjuvanted influenza vaccination, assigned by randomisation
Outcomes	1. Vaccine immunogenicity reported as seroconversion rate, seroprotection rate or geometric mean titres 2. Laboratory‐confirmed influenza infections 3. Mortality related to influenza infections 4. All‐cause mortality 5. Hospitalisations attributed to influenza infections 6. Any hospitalisation 7. Adverse events
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated schedule in blocks of four
Allocation concealment (selection bias)	Low risk	Central randomisation
Incomplete outcome data (attrition bias) All outcomes	Low risk	No patients lost to follow up for the mortality outcome.
Selective reporting (reporting bias)	Low risk	No significant differences in the secondary outcomes added to the manuscript after registration
Other bias	Low risk	No baseline imbalances, funding not mentioned, sample size achieved
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and personnel were not blinded, but low risk because of objective outcomes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Assessors of adverse events and lab workers were blinded

Vinograd 2013

Methods	Prospective observational cohort study Location: Israel
Participants	Solid 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
Interventions	Patients 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.
Outcomes	1. A composite of hospitalisations for fever or acute respiratory infection; and/or pneumonia necessitating antibiotic treatment; and/or chemotherapy interruptions related 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 hospitalisation and hospitalisation days 7. Antibiotic treatment necessity in hospitalisation 8. All delays in planned chemotherapy courses
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Non‐random
Allocation concealment (selection bias)	High risk	Non‐random
Incomplete outcome data (attrition bias) All outcomes	Low risk	All outcomes reported fully
Selective reporting (reporting bias)	Low risk	None identified
Other bias	Low risk	Controlled for cancer stage and functional capacity, funded by an internal grant, sample size achieved
Blinding of participants and personnel (performance bias) All outcomes	High risk	None blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	None blinded

HSCT: haematopoietic stem cell transplantation; CML: chronic myelogenous leukaemia; MM: multiple myeloma; NHL: non‐Hodgkin's lymphoma

Characteristics of excluded studies [ordered by study ID]

Jump to:

included studies

Study	Reason for exclusion
Adell 2002	All participants vaccinated
Anderson 1999	All participants vaccinated
Avetisyan 2008	All participants vaccinated
Ayoola 2016	All participants vaccinated
Baluch 2013	All participants vaccinated
Bedognetti 2009	Lymphoma participants compared to healthy participants
Bedognetti 2010	Lymphoma participants compared to healthy participants
Branagan 2015	All participants vaccinated
Branagan 2016	Comparing different doses of influenza vaccine
Branagan 2017	All participants vaccinated
Brydak 1999	All participants vaccinated
Brydak 2001	Healthy participants not vaccinated compared to breast cancer participants vaccinated
Brydak 2006	Lymphoma participants compared to healthy participants
Buccalosi 1995	All participants vaccinated Lymphoma participants compared to healthy participants
Centkowski 2007	All participants vaccinated Lymphoma participants compared to healthy participants
Chadha 2009	All participants vaccinated
De Lavallade 2011	Comparison to healthy participants
Dhedin 2014	Immunogenecity of vaccine compared to infection
Engelhard 1993	All participants vaccinated Comparing different doses of influenza vaccine
Feery 1977	Comparison to healthy participants
Ganz 1978	Comparison to healthy participants
Gribabis 1994	All participants vaccinated
Hahn 2015	Comparing different doses of influenza vaccine
Hodges 1979	Comparison to healthy participants
Issa 2011	All participants vaccinated
Jamshed 2016	Comparing different doses of influenza vaccine
Jo 2009	Comparing different doses of influenza vaccine
Keam 2017	All participants vaccinated
Lachenal 2010	Vaccination rate in haematological participants
Lankes 2009	Association between influenza vaccination and risk of developing Non‐Hodgkin lymphoma
Ljungman 2005	Comparing different doses of influenza vaccine
Ljungman 2015	Comparing different types of vaccines in different seasons
Lo 1993	Comparing different doses of influenza vaccine
Mazza 2005	All participants vaccinated Lymphoma participants compared to healthy participants
Mulder 2009	All participants vaccinated Comparison to healthy participants
Nakashima 2017	All participants vaccinated, healthy controls
Nordoy 2002	All participants vaccinated
Ortbals 1977	All participants vaccinated
Puthillath 2011	All participants vaccinated Serological outcomes only
Rapezzi 2003	All participants vaccinated Lymphoma participants compared to healthy participants
Robertson 2000	Myeloma participants vaccinated compared to healthy participants' serum
Safdar 2006	Comparing different influenza vaccines in Non‐Hodgkin lymphoma patients
Schafer 1979	All participants vaccinated Haematological participants compared to healthy participants
Seidel 2011	All participants vaccinated
Shildt 1979	All participants vaccinated
Spies 2008	No 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 2010	All participants vaccinated
Stiver 1978	All participants vaccinated
Sun 2016	All participants vaccinated
Takata 2009	All participants vaccinated
Van der Velden 2001	All participants vaccinated
Villa 2013	Comparing different doses of influenza vaccine
Wumkes 2013	All participants vaccinated
Xu 2009	All participants vaccinated Comparison to healthy participants
Yalc 2010	All participants vaccinated

Data and analyses

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Comparison 1. Influenza vaccine versus none

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality Show forest plot	3		Odds Ratio (Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.1 Comparison 1 Influenza vaccine versus none, Outcome 1 All‐cause mortality.
1.1 Non‐randomised, adjusted, events/person‐years	1		Odds Ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Non‐randomised, adjusted, events/person	1		Odds Ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Randomised, events/person	1		Odds Ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Influenza‐like illness Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.2 Comparison 1 Influenza vaccine versus none, Outcome 2 Influenza‐like illness.
2.1 Randomised, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Non‐randomised, unadjusted, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Confirmed influenza Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.3 Comparison 1 Influenza vaccine versus none, Outcome 3 Confirmed influenza.
3.1 Non‐randomised, unadjusted, events/person‐years	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Non‐randomised, unadjusted, events/persons with ILI	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Non‐randomised, unadjusted, events/persons	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Randomised, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Pneumonia Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.4 Comparison 1 Influenza vaccine versus none, Outcome 4 Pneumonia.
4.1 Randomised, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Non‐randomised, unadjusted, events/person‐years	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Non‐randomised, unadjusted, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Any hospitalisation Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.5 Comparison 1 Influenza vaccine versus none, Outcome 5 Any hospitalisation.
5.1 Randomised, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Non‐randomised, unadjusted, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Influenza‐related mortality Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.6 Comparison 1 Influenza vaccine versus none, Outcome 6 Influenza‐related mortality.
6.1 Randomised, events/person	2		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Non‐randomised, unadjusted, events/person‐years	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 2. Adjuvanted vaccine versus non‐adjuvanted vaccine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.1 Comparison 2 Adjuvanted vaccine versus non‐adjuvanted vaccine, Outcome 1 All‐cause mortality.
2 Confirmed influenza Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.2 Comparison 2 Adjuvanted vaccine versus non‐adjuvanted vaccine, Outcome 2 Confirmed influenza.
3 Any hospitalisation Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.3 Comparison 2 Adjuvanted vaccine versus non‐adjuvanted vaccine, Outcome 3 Any hospitalisation.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Influenza vaccine versus none, Outcome 1 All‐cause mortality.

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Analysis 1.2

Comparison 1 Influenza vaccine versus none, Outcome 2 Influenza‐like illness.

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Analysis 1.3

Comparison 1 Influenza vaccine versus none, Outcome 3 Confirmed influenza.

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Analysis 1.4

Comparison 1 Influenza vaccine versus none, Outcome 4 Pneumonia.

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Analysis 1.5

Comparison 1 Influenza vaccine versus none, Outcome 5 Any hospitalisation.

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Analysis 1.6

Comparison 1 Influenza vaccine versus none, Outcome 6 Influenza‐related mortality.

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Analysis 2.1

Comparison 2 Adjuvanted vaccine versus non‐adjuvanted vaccine, Outcome 1 All‐cause mortality.

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Analysis 2.2

Comparison 2 Adjuvanted vaccine versus non‐adjuvanted vaccine, Outcome 2 Confirmed influenza.

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Analysis 2.3

Comparison 2 Adjuvanted vaccine versus non‐adjuvanted vaccine, Outcome 3 Any hospitalisation.

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Summary of findings for the main comparison. Influenza vaccine compared to no vaccine for immunosuppressed adults with cancer

Influenza vaccine compared to no vaccine for immunosuppressed adults with cancer
Patient or population: immunosuppressed adults with cancer Setting: outpatients Intervention: influenza vaccine Comparison: no vaccine
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with no vaccine	Risk with influenza vaccine
All‐cause mortality, solid cancers Follow‐up: range 4 months to 12 months	Study population		OR 0.88 (0.78 to 1.00)	1577 (1 observational study)	⊕⊝⊝⊝ VERY LOW ^{1 2 3}	Earle 2003
	417 per 1,000	387 per 1,000 (359 to 417)
All‐cause mortality, solid and haematological malignancies Follow‐up: range 5 months to 7 months	Study population		OR 0.42 (0.24 to 0.75)	806 (1 observational study)	⊕⊝⊝⊝ VERY LOW ^{3 4}	Vinograd 2013
	456 per 1,000	260 per 1,000 (167 to 386)
All‐cause mortality, allogeneic BMT Follow‐up: mean 6 months	Study population		OR 1.25 (0.43 to 3.62)	78 (1 RCT)	⊕⊕⊝⊝ LOW ^{5 6}	Ambati 2015
	211 per 1,000	250 per 1,000 (103 to 491)
*The risk in the intervention group (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). BMT: bone marrow transplantation; CI: Confidence interval; OR: Odds ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ observational study, low Newcastle Ottawa score ² confidence interval up to 1 ³ observational study ⁴ observational study, high Newcastle Ottawa score ⁵ reporting bias‐ no trial registry, vague description of outcomes in methods, small numbers ⁶ wide confidence interval crossing 1

Summary of findings for the main comparison. Influenza vaccine compared to no vaccine for immunosuppressed adults with cancer

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Summary of findings 2. Adjuvanted influenza vaccine compared to non‐adjuvanted influenza vaccine in immunosuppressed adults with cancer

Adjuvanted influenza vaccine compared to non‐adjuvanted influenza vaccine in immunosuppressed adults with cancer
Patient or population: immunosuppressed adults with cancer Setting: outpatients Intervention: adjuvanted influenza vaccine Comparison: non‐adjuvanted influenza vaccine
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with non‐adjuvanted influenza vaccine	Risk with adjuvanted influenza vaccine
All‐cause mortality, allogeneic BMT, Follow‐up: mean 6 months	Study population		RR 0.54 (0.05 to 5.73)	73 (1 RCT)	⊕⊕⊝⊝ LOW ¹	Natori 2017
	53 per 1,000	28 per 1,000 (3 to 302)
*The risk in the intervention group (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; RCT: randomised controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Small sample size, large confidence intervals

Summary of findings 2. Adjuvanted influenza vaccine compared to non‐adjuvanted influenza vaccine in immunosuppressed adults with cancer

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Table 1. Influenza frequency and related outcomes in HSCT recipients and adults with cancer

Ref.	Type of malignancy (influenza years)	No of cases	Influenza cases	Outcome
Ljungman 2001	Allogeneic BMT/HSCT recipients (1997 to 1998)	819	1.7%	Deaths 29%
	Autologous BMT/HSCT recipients (1997 to 1998)	1154	0.2%	Deaths 0%
	Allogeneic BMT/HSCT recipients (1997 to 2000)	>819		Deaths 23%
	Autologous BMT/HSCT recipients (1997 to 2000)	>1154		Deaths 22%
Hassan 2003	Allogeneic BMT/HSCT recipients (1996 to 2001)	230	2.2%	Deaths 20%
Hassan 2003	Autologous BMT/HSCT recipients (1996 to 2001)	396	0%
Nichols 2004	HSCT recipients (within 120 days after transplantation) (1989 to 2002)	4797	1.3%	Deaths 10% Pneumonia 29%
Machado 2003	HSCT recipients (URTI symptoms present) (2001 to 2002)	179	23%	Deaths 0%
Chemaly 2006	HSCT recipients AND haematologic malignancies (retrospective study of patients with laboratory‐confirmed viral respiratory infection) (2000 to 2002)	343	33%	Deaths 4% Pneumonia 30%
	HSCT recipients	230	29%
	Leukaemia	61	33%
	Lymphoma	37	51%
	Multiple myeloma	15	40%
Yousuf 1997	CLL /acute leukaemia (hospitalised patients) (1993 to 1994)	45	33%	Deaths 27% Pneumonia 80%
Elting 1995	CLL /acute leukaemia (1991 to 1992)	37	11%	Deaths 25% Pneumonia 75%
Redelman‐Sidi 2010	Solid cancers (H1N1 2009 pandemic)	226	7%	0% Deaths
Redelman‐Sidi 2010	Haematologic malignancies (H1N1 2009 pandemic)	167 (96 HSCT)	17% (22%)	0% Deaths
Ljungman 2011	HSCT recipients (prospective study of patients with laboratory‐confirmed H1N1 infection) (H1N1 2009 pandemic)	286		Deaths 6% Pneumonia 33%
Chemaly 2012	Solid cancers (retrospective study of patients with laboratory‐confirmed H1N1 infection) (H1N1 2009 pandemic)	115		Deaths 9.5% Pneumonia 23%
BMT: bone marrow transplantation; CLL: chronic lymphocytic leukaemia; HSCT: haematopoietic stem cell transplantation; URTI: upper respiratory tract infection

Table 1. Influenza frequency and related outcomes in HSCT recipients and adults with cancer

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Table 2. Newcastle‐Ottawa Grading

	Selection				Comparability	Outcome			Total stars score
	Representativeness of the exposed cohort	Selection of the non‐exposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability *	Assessment of outcome	Was follow‐up long enough for outcomes to occur?	Adequacy of follow‐up of cohorts **
Earle 2003	c	a	a	a	No	d ***	a	a	5
Machado 2005	c	a	a	a	No	b	a	a	6
Vinograd 2013	b	a	a+b	a	a+b	b+c	a	a	10
* 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 2. Newcastle‐Ottawa Grading

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Table 3. Summary of Main Outcomes ‐ vaccine versus no vaccine

Outcome

Design

All‐cause mortality

Influenza‐like‐ illness

Influenza‐ related mortality

Confirmed influenza

Pneumonia

Any hospitalisation

Chemotherapy interruptions

GMT

Vaccination status

Yes

No

Yes

No

Yes

No

Yes

No

Yes

No

Yes

No

Yes

No

Earle 2003

Retrospective observational

Cox adjusted HR 0.88 (95% CI 0.78 to 1), 626 versus 951 py *

0/626 py

2/951 py

0/626 py

3/951 py

7/626 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 2005

Retrospective case‐control

2/19 *

12/24 *

Musto 1997

Randomised, open‐label

8/25 *

18/25 *

0/25

2/25

0/25

4/25

2/25 *

12/25 *

Vinograd 2013

Prospective observational

MV adjusted OR 0.42 (95% CI 0.24 to 0.75) (387 versus 419p); MV adjusted OR in propensity‐matched cohort 0.42 (95% CI 0.24 to 0.76) (218p versus 218p)

134/387

137/419

2/387

4/419

81/387

78/419

183/387

205/419

97/387

116/419

Ambati 2015

Randomised, open‐label

OR 1.25 (95%CI 0.43‐3.62)

2/40

2/38

3/40

4/38

15*,

30*,

110

***

10*, 12.5*, 60

***

py= persons years

* denoted statistically significant difference, P < 0.05

** mean interval between chemotherapy bills

*** data is for A/H1N1, A/H3N2 and B respectively

CI: confidence interval;GMT: geometric mean titre. (Data are for 30 days post vaccination); HR: hazard ratio; OR: odds ratio;

Table 3. Summary of Main Outcomes ‐ vaccine versus no vaccine

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Table 4. Summary of Main Outcomes ‐ adjuvanted versus non‐adjuvanted

Outcome	Design	All‐cause mortality		Influenza‐related mortality		Confirmed influenza		Any hospitalisation		GMT
Vaccination status		Adjuvanted	Non‐adjuvanted	Adjuvanted	Non‐adjuvanted	Adjuvanted	Non‐adjuvanted	Adjuvanted	Non‐adjuvanted	Adjuvanted	Non‐adjuvanted
Natori 2017	Randomised, open‐label	1/35	2/38	0/35	0/38	5/35	3/38	8/35	11/38	319.6, 480.7, 298.9 *	195.9, 359.3, 240.5 *
* data is for A/H1N1, A/H3N2 and B respectively GMT: geometric mean titre. (Data are for 30 days post vaccination).

Table 4. Summary of Main Outcomes ‐ adjuvanted versus non‐adjuvanted

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Comparison 1. Influenza vaccine versus none

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality Show forest plot	3		Odds Ratio (Fixed, 95% CI)	Totals not selected

1.1 Non‐randomised, adjusted, events/person‐years	1		Odds Ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Non‐randomised, adjusted, events/person	1		Odds Ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Randomised, events/person	1		Odds Ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Influenza‐like illness Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 Randomised, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Non‐randomised, unadjusted, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Confirmed influenza Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Non‐randomised, unadjusted, events/person‐years	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Non‐randomised, unadjusted, events/persons with ILI	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Non‐randomised, unadjusted, events/persons	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Randomised, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Pneumonia Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 Randomised, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Non‐randomised, unadjusted, events/person‐years	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Non‐randomised, unadjusted, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Any hospitalisation Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.1 Randomised, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Non‐randomised, unadjusted, events/person	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Influenza‐related mortality Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.1 Randomised, events/person	2		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Non‐randomised, unadjusted, events/person‐years	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Influenza vaccine versus none

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Comparison 2. Adjuvanted vaccine versus non‐adjuvanted vaccine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Confirmed influenza Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Any hospitalisation Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Adjuvanted vaccine versus non‐adjuvanted vaccine

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References

References to studies included in this review

Ambati 2015 {published data only}

Earle 2003 {published data only}

Machado 2005 {published data only}

Musto 1997 {published data only}

Natori 2017 {published data only}

Vinograd 2013 {published data only}

References to studies excluded from this review

Adell 2002 {published data only}

Anderson 1999 {published data only}

Avetisyan 2008 {published data only}

Ayoola 2016 {published data only}

Baluch 2013 {published data only}

Bedognetti 2009 {published data only}

Bedognetti 2010 {published data only}

Branagan 2015 {published data only}

Branagan 2016 {published data only}

Branagan 2017 {published data only}

Brydak 1999 {published data only}

Brydak 2001 {published data only}

Brydak 2006 {published data only}

Buccalosi 1995 {published data only}

Centkowski 2007 {published data only}

Chadha 2009 {published data only}

De Lavallade 2011 {published data only}

Dhedin 2014 {published data only}

Engelhard 1993 {published data only}

Feery 1977 {published data only}

Ganz 1978 {published data only}

Gribabis 1994 {published data only}

Hahn 2015 {published data only}

Hodges 1979 {published data only}

Issa 2011 {published data only}

Jamshed 2016 {published data only}

Jo 2009 {published data only}

Keam 2017 {published data only}

Lachenal 2010 {published data only}

Lankes 2009 {published data only}

Ljungman 2005 {published data only}

Ljungman 2015 {published data only}

Lo 1993 {published data only}

Mazza 2005 {published data only}

Mulder 2009 {published data only}

Nakashima 2017 {published data only}

Nordoy 2002 {published data only}

Ortbals 1977 {published data only}

Puthillath 2011 {published data only}

Rapezzi 2003 {published data only}

Robertson 2000 {published data only}

Safdar 2006 {published data only}

Schafer 1979 {published data only}

Seidel 2011 {published data only}

Shildt 1979 {published data only}

Spies 2008 {published data only}

Spitaleri 2010 {published data only}

Stiver 1978 {published data only}

Sun 2016 {published data only}

Takata 2009 {published data only}

Van der Velden 2001 {published data only}

Villa 2013 {published data only}

Wumkes 2013 {published data only}

Xu 2009 {published data only}

Yalc 2010 {published data only}

Additional references

Alistair 2002

Anema 2008

Angelo 2004

Arrowood 2002

Beck 2012

Black 2015

Casper 2010

CDC Cancer prevention 2017

CDC Flu Vaccination 2017

CDC MMWR 2010

CDC Surveillance 2016

Chemaly 2006

Chemaly 2012