Influenza vaccines in immunosuppressed adults with cancer Edited (no change to conclusions)

Abstract

Abstract Background

This is an update of the Cochrane review published in 2013, Issue 10.

Immunosuppressed cancer patients are at increased risk of serious influenza‐related complications. Guidelines, therefore, recommend influenza vaccination for these patients. However, data on vaccine effectiveness in this population are lacking, and the value of vaccination in this population remains unclear.

Objectives

To assess the effectiveness of influenza vaccine in immunosuppressed adults with malignancies. The primary review outcome is all‐cause mortality, preferably at the end of the influenza season. Influenza‐like illness (ILI, a clinical definition), confirmed influenza, pneumonia, any hospitalisations, influenza‐related mortality and immunogenicity were defined as secondary outcomes.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and LILACS databases up to May 2017. We searched the following conference proceedings: ICAAC, ECCMID, IDSA (infectious disease conferences), ASH, ASBMT, EBMT (haematological), and ASCO (oncological) between the years 2006 to 2017. In addition, we scanned the references of all identified studies and pertinent reviews. We searched the websites of the manufacturers of influenza vaccine. Finally, we searched for ongoing or unpublished trials in clinical trial registry databases.

Selection criteria

Randomised controlled trials (RCTs), prospective and retrospective cohort studies and case‐control studies were considered, comparing inactivated influenza vaccines versus placebo, no vaccination or a different vaccine, in adults (16 years and over) with cancer. We considered solid malignancies treated with chemotherapy, haematological cancer patients treated or not treated with chemotherapy, cancer patients post‐autologous (up to six months after transplantation) or allogeneic (at any time) haematopoietic stem cell transplantation (HSCT).

Data collection and analysis

Two review authors independently assessed the risk of bias and extracted data from included studies adhering to Cochrane methodology. Meta‐analysis could not be performed because of different outcome and denominator definitions in the included studies.

Main results

We identified six studies with a total of 2275 participants: five studies comparing vaccination with no vaccination, and one comparing adjuvanted vaccine with non‐adjuvanted vaccine. Three studies were RCTs, one was a prospective observational cohort study and two were retrospective cohort studies.

For the comparison of vaccination with no vaccination we included two RCTs and three observational studies, including 2202 participants. One study reported results in person‐years while the others reported results per person. The five studies were performed between 1993 and 2015 and included adults with haematological diseases (three studies), patients following bone marrow transplantation (BMT) (two studies) and solid malignancies (three studies).

One RCT and two observational studies reported all‐cause mortality; the RCT showed similar mortality rates in both arms (odds ratio (OR) 1.25 (95% CI 0.43 to 3.62; 1 study, 78 participants, low‐certainty evidence)); and the observational studies demonstrated a significant association between vaccine receipt and lower risk of death, adjusted hazard ratio 0.88 (95% CI 0.78 to 1; 1 study, 1577 participants, very low‐certainty evidence) in one study and OR 0.42 (95% CI 0.24 to 0.75; 1 study, 806 participants, very low‐certainty evidence) in the other. One RCT reported a reduction in ILI with vaccination, while no difference was observed in one observational study. Confirmed influenza rates were lower with vaccination in one RCT and the three observational studies, the difference reaching statistical significance in one. Pneumonia was observed significantly less frequently with vaccination in one observational study, but no difference was detected in another or in the RCT. One RCT showed a reduction in hospitalisations following vaccination, while an observational study found no difference. No life‐threatening or persistent adverse effects from vaccination were reported. The strength of evidence was limited by the low number of included studies and by their low methodological quality and the certainty of the evidence for the mortality outcome according to GRADE was low to very low.

For the comparison of adjuvanted vaccine with non‐adjuvanted vaccine, we identified one RCT, including 73 patients. No differences were found for the primary and all secondary outcomes assessed. Mortality risk ratio was 0.54 (95% CI 0.05 to 5.73; low‐certainty evidence) in the adjuvanted vaccine group. The quality of evidence was low due to the small sample size and the large confidence intervals for all outcomes.

Authors' conclusions

Observational data suggest lower mortality and infection‐related outcomes with influenza vaccination. The strength of evidence is limited by the small number of studies and low grade of evidence. It seems that the evidence, although weak, shows that the benefits overweigh the potential risks when vaccinating adults with cancer against influenza. However, additional placebo or no‐treatment controlled RCTs of influenza vaccination among adults with cancer is ethically questionable.There is no conclusive evidence regarding the use of adjuvanted versus non‐adjuvanted influenza vaccine in this population.

Author(s)

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

Abstract

Plain language summary

Influenza (flu) vaccination for preventing influenza in adults with cancer

Background
 Adults with cancer are prone to serious complications from influenza, more than healthy adults. The influenza vaccine protects against influenza and its complications. However, its effectiveness among people with cancer is unclear, as immune dysfunction that accompanies cancer as a result of chemotherapy might lower immune response to the vaccine. People with cancer, therefore, do not have clear information on the importance and effectiveness of the vaccine.

The aim of the review
 This review focused on the effectiveness of influenza vaccination in adults with cancer who have a suppressed immune system because of cancer or chemotherapy. We searched the literature up to May 2017.

What are the main findings?
 We identified six clinical studies (2275 participants) addressing this question, half of which were randomised controlled trials, where patients were randomly selected to get or not to get the vaccine. Two other studies showed that adults with cancer who were vaccinated were found to have lower rates of death, but these studies were not randomised. One small randomised study showed a similar mortality rate in vaccinated and non‐vaccinated patients. Pooling (combining) results from the different studies was not possible because of different methods or different ways the results were reported. There was a lower rate of influenza‐like illness (any febrile respiratory illness), pneumonia, confirmed influenza and hospitalisation for any reason, among vaccinated people in at least one study. No side effects to the vaccine were reported in these studies. The review also included a trial comparing the regular vaccine to a vaccine containing an adjuvant that is supposed to increase the immune response. This randomised trial was small and did not find differences in all clinical outcomes examined.

Quality of the evidence
 The strength of evidence is limited by the low number of studies and by their low methodological quality (high risk of bias).

What are the conclusions?
 It is unlikely that there will be any future large‐scale controlled trials to investigate this issue. The current evidence, although weak, suggests a benefit for influenza vaccination amongst adults with cancer and the vaccine was not found to be harmful. Influenza vaccines given to adults with cancer contain an inactivated virus that cannot cause influenza or other viral infection.

Author(s)

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

Reviewer's Conclusions

Authors' conclusions

Implications for practice

The existing evidence on the effectiveness of influenza vaccine in immune‐suppressed adults with malignancies is mostly observational, incomplete and of low quality. It was previously shown that Influenza‐related complications are more common among these adults compared to the general population, including hospitalisation and death. Although the data available are sparse and of low quality, there is no harm in the vaccine and possible benefit with regard to survival, confirmed influenza, influenza‐like illness, pneumonia and hospitalisations. Data on all‐cause mortality from two cohort studies showed significantly lower mortality in vaccinated participants, whereas the one randomised controlled trial (RCT) that evaluated this showed no significant benefit or harm. The evidence (though weak) is in favour of vaccinating this population. The summary of the available evidence should be used to encourage care givers and adults with cancer to accept yearly influenza vaccination.

Unfortunately, no recommendations can be made with regard to the use of adjuvanted influenza vaccine among adults with cancer. The study included in our review, though an RCT, included few patients and showed no significant improvements in clinical and non‐clinical endpoints.

Implications for research

Performing a placebo or no‐treatment controlled RCT of influenza vaccination among adults with cancer is ethically questionable. We believe that the vaccine carries some degree of benefit and have no reason to believe that the vaccine is harmful or that adverse events will be different than those observed in the general population. In place of RCTs, we suggest well‐conducted observational studies. Such studies should encompass people of a defined age group, and a variety of malignancies treated with different modalities (chemotherapy, immunotherapy, targeted therapy, and especially haematological malignancies, autologous or allogeneic stem cell transplant). These kind of studies should also include many influenza seasons (many years of follow‐up) and would allow a better propensity score to be done. Studies should have a minimal risk of bias, the outcomes employed should be clinically important and include all‐cause mortality, confirmed influenza, influenza‐like illness, pneumonia and influenza‐related death. Exact data on immunological response to vaccination, how influenza is confirmed, hospitalisations and hospital days, chemotherapy interruptions, adverse effects of vaccination, should be collected. A retrospective comparison of influenza vaccine effectiveness in years with a good match versus years with a poor match of vaccine and circulating influenza strains could also be useful.

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