key: cord-318753-ribybqfo
authors: Kwok, C. S.; Aslam, S.; Kontopantelis, E.; Myint, P. K.; Zaman, M. J. S.; Buchan, I.; Loke, Y. K.; Mamas, M. A.
title: Influenza, influenza‐like symptoms and their association with cardiovascular risks: a systematic review and meta‐analysis of observational studies
date: 2015-05-04
journal: Int J Clin Pract
DOI: 10.1111/ijcp.12646
sha: 
doc_id: 318753
cord_uid: ribybqfo

AIMS: To synthesise the evidence relating influenza and influenza‐like symptoms to the risks of myocardial infarction (MI), heart failure (HF) and stroke. METHODS: We conducted a systematic review and meta‐analysis of the evidence relating influenza and influenza‐like symptoms to the risks of MI, HF and stroke. We systematically searched all MEDLINE and EMBASE entries up to August 2014 for studies of influenza vs. the cardiovascular outcomes above. We conducted random effects meta‐analysis using inverse variance method for pooled odds ratios (OR) and evaluated statistical heterogeneity using the I (2) statistic. RESULTS: We identified 12 studies with a total of 84,003 participants. The pooled OR for risk of MI vs. influenza (serologically confirmed) was 1.27 (95% CI, confidence interval 0.54–2.95), I (2) = 47%, which was significant for the only study that adjusted for confounders (OR 5.50, 95% CI 1.31–23.13). The pooled OR for risk of MI vs. influenza‐like symptoms was 2.17 (95% CI 1.68–2.80), I (2) = 0%, which was significant for both unadjusted (OR 2.23, 95% CI 1.65–3.01, five studies) and adjusted studies (OR 2.01, 95% CI 1.24–3.27, two studies). We found one study that evaluated stroke risk, one study in patients with HF, and one that evaluated mortality from MI – all of these studies suggested increased risks of events with influenza‐like symptoms. CONCLUSIONS: There is an association between influenza‐like illness and cardiovascular events, but the relationship is less clear with serologically diagnosed influenza. We recommend renewed efforts to apply current clinical guidelines and maximise the uptake of annual influenza immunisation among patients with cardiovascular diseases, to decrease their risks of MI and stroke.

• We conducted random effects meta-analysis using inverse variance method for pooled odds ratios (OR) and evaluated statistical heterogeneity using the I 2 statistic.

Message for the clinic • There is an apparent association between influenza-like illness and adverse cardiovascular events.

During a typical flu season in England and Wales, there are around 1.1 million extra consultations for acute respiratory infections, over 3000 excess hospital admissions, and around 12,500 deaths (1) . In the H1N1 influenza pandemic, around 540,000 people in England had symptomatic H1N1 infection, with a case fatality rate of 26 deaths per 100,000 cases (2) .

There is some observational evidence that major cardiovascular events are a prominent mechanism in deaths linked to influenza (3, 4) . Excess mortality during influenza epidemics in Europe and the USA in the early 1900s was indeed attributed to causes other than influenza, such as heart disease (5), a finding replicated in more contemporary studies (6) (7) (8) . Stroke also appears to be more common after a respiratory infection (9) (10) (11) .

While some studies suggests that influenza may be a precursor to incident cardiovascular events, there remain inconsistencies in the literature. Several reviews have evaluated the potential for influenza to trigger cardiovascular events (3, 8, (12) (13) (14) . These articles have summarised cardiovascular manifestations of influenza and described the direct effects of the virus on the myocardium (3, 14) , as well as the potential mechanisms of acute coronary syndrome with infection (13) .

While existing studies have shown some evidence that influenza may be associated with cardiovascular disease (CVD) there has been no published metaanalysis of the association. In addition, these studies focused on coronary heart disease, while less is known about stroke and heart failure (HF).

In view of the uncertainty regarding the association between influenza and influenza-like symptoms and risk of CVD, we conducted a systematic review and meta-analysis to quantify the risk of myocardial infarction (MI), HF and stroke among patients recorded as having influenza and influenza-like symptoms.

We selected studies that evaluated the association between influenza and adverse cardiovascular outcomes. We included all study designs and placed no restriction on the definition of influenza that could be based on recording flu-like symptoms or serologically confirmed cases. The end-points were considered were MI, HF, stroke and cardiovascular death.

We searched (via OVID) MEDLINE and EMBASE from inception up to the end of August 2014 with no language limitations and using the broad free-text and indexing search terms [(influenza or flu) AND ((myocardial infarction OR acute coronary syndrome OR ischemic heart disease OR ischaemic heart disease) OR (heart failure or cardiac failure or left ventricular impairment) OR (stroke OR cerebrovascular disease or cerebrovascular accident) OR (cardiac death OR cardiovascular death OR cardiovascular mortality)]. Additional relevant studies were identified by checking the bibliographies of included articles.

Two reviewers (CSK and SU) evaluated all titles and abstracts for studies that met the inclusion criteria and studies that did not clearly meet the selection criteria were excluded. One senior author (YKL) checked the potential inclusions and full reports (where available) of potentially relevant studies were retrieved and independently checked for eligibility. Two reviewers independently extracted data from included studies into a proforma spreadsheet covering study design; study location; characteristics of participants; definition of influenza; outcome ascertainment and results. The spreadsheet data were then checked for completeness and accuracy by a senior reviewer (YKL). Two reviewers (CSK and SU) then independently extracted the number of events and denominators from the sources papers, thereby enabling calculations of crude (unadjusted) estimates of the risk of adverse events among patients with influenza. Where raw results were not available, we collected results that were the most adjusted risk estimates [adjusted relative risk, odds ratio (OR), or hazard ratios] for cardiovascular events with influenza. Any differences were reconciled through the arbitration and further investigation of a senior clinical researcher (YKL). Authors of manuscripts were contacted to seek further information where necessary.

The quality of included studies was evaluated using a risk of bias assessment including: ascertainment of exposure to influenza, ascertainment of selected cardiovascular outcomes and adjustments for potential confounders. Overall risk of bias of studies was deemed to be low if all three categories were satisfied and deemed to be moderate risk of bias if two categories were satisfied and high risk of bias if zero or one categories were satisfied. Where there was no evidence of substantial heterogeneity and more than 10 studies available for meta-analysis, we used funnel plots to assess publication bias (15) .

We used RevMan 5.2. (Nordic Cochrane Centre, Copenhagen, Denmark) to conduct a DerSimonian-Laird random effects meta-analysis using an inverse variance weighting approach, to calculate a pooled OR. We assumed asymptotic convergence of risk ratio and OR as the proportion of adverse outcomes was low (16) . We evaluated both adjusted and unadjusted data from primary studies, although we preferentially used adjusted data where available. We stratified the main analysis based on the measures of ascertaining influenza (e.g. laboratory serology tests or based on clinical presentation suggesting influenza-like illness) and use of adjustments to account for potential confounders. If different types of influenza were reported, we used the category with the largest number of patients.

Statistical heterogeneity was assessed using I 2 statistic (17) , with I 2 values of 30-60% representing a moderate level of heterogeneity.

Statistical results are presented as the main effect with 95% confidence intervals (CIs) in braces unless otherwise specified.

We identified 12 studies that met the inclusion criteria (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) . Details of the study selection are shown in Figure S1 . There were seven case-control studies, two case-cross-over studies, two cohort studies and one self-controlled case-series study. There were a total of 84,003 participants. The mean age from four studies ranged from 42 to 65 years and median age ranged from 64 to 75 years from four other studies. The percentage of male patients ranged from 42% to 100%. Details are shown in Table 1 .

The study quality assessment is shown in Table S1 . The methods for ascertaining exposure to influenza included the use of questionnaires, clinical assessments, review of patient records and laboratory testing. Seven studies used well-characterised methods of ascertaining influenza exposure blood tests (18, 20, (22) (23) (24) , lung tissue testing (26) and a validated algorithm (19) . Apart from one study where ascertainment of outcome was unclear (29) , all studies reported methods that could reliably identify cardiovascular events. Three studies reported use of adjustments for more than two potential confounders (18, 27, 28) . In terms of risk of bias, one study was classified as low risk of bias (18) and three studies were classified as high risk of bias (21, 25, 29) .

Influenza exposure and cardiovascular outcome evaluation results are shown in Table 2 . Influenza exposure was defined by serology or laboratory tests in four studies while in the other five studies it was based on symptoms and questionnaires. In Madjid et al., influenza epidemics were defined as weekly acute respiratory disease morbidity exceeding the predefined epidemic thresholds (21) . The reporting of the follow-up or timing of influenza exposure was variable. Three studies did not report any information on this (18, 20, 26) , but among the other studies, influenza exposure ranged from the preceding week to preceding 3 months. Finally, nine studies evaluated MI as the cardiovascular outcome while one study evaluated death from MI (21), one study evaluated ischaemic stroke (19) and one study evaluated HF (24) .

Of the nine studies with a MI outcome, we excluded the study by Pesonen et al. since it compared the risk of MI at different influenza symptom levels, rather than symptoms vs. no symptoms (25) . The remaining eight studies were then stratified into four studies, which used serology or laboratory tests to confirm influenza and seven studies that diagnosed influenza based on symptoms or clinical presentation. The pooled OR for the risk of MI with serologically diagnosed influenza was OR 1.27 (95% CI, 0.54-2.95), I 2 = 47% (956 participants), which was significant for the only study that adjusted for confounders (OR 5.50, 95% CI 1.31-23.13; Figure 1 ). The pooled OR for risk of MI with influenza-like symptoms was 2.17 (95% CI 1.68-2.80), I 2 = 0%, 6658 participants, which was significant for both unadjusted OR 2.23 (95% CI 1.65-3.01, five studies, 2597 participants) and adjusted (OR 2.01, 95% CI 1.24-3.27, two studies, 4061 participants) studiessee Figure 2 .

Pesonen et al. found that two to three vs. one or no symptoms of influenza-like illness was associated with increased risk of MI (OR 3.8, 95% CI 1.4-10.8) (25) .

The study by Nicholls et al. was the only study that evaluated the risk of HF with influenza (24) . This study found that three of eight participants who tested positive for influenza A had HF (left ventricular failure or congestive cardiac failure) while four of the other 51 participants had HF. The crude OR for risk of HF from this study was 7.05 (95% CI 1. 22-40.90 ).

The study by Luna et al. evaluated the timing of flulike illness and risk of ischaemic stroke (19) . They found that the greatest risk was present within the first 15 days (adjusted OR 6.5, 95% CI 2.2-19.7) and decreased in magnitude with prolonged duration to adjusted OR 3.3 (95% CI 1.9-5.8) at 90 days.

Madjid et al. conducted a study that was not included in the meta-analysis because it evaluated outcomes indirectly, namely autopsy rates of CVD vs. influenza epidemics (21) . This was the only study that evaluated risk of cardiovascular mortality and found that that influenza epidemics were associated with increased odds of death from acute MI (OR 1.30, 95% CI 1.08-1.56).

Our meta-analysis suggests that influenza-like illness is associated with a twofold increase in MI. The risk of MI with serologically defined influenza is less evident, however, the only study that adjusted for potential confounders showed an increased risk of MI with positive influenza tests. In addition, there is limited evidence that flu-like illness precipitates both stroke and HF events, although these observations are based on just single publications, thus warranting further study. A major challenge of studies which associate flulike symptoms and CVD is the spectrum of viral infections that can initiate flu-like symptoms. A review of influenza-like illness suggests that respiratory syncytial virus, rhinovirus, adenovirus, parainfluenza viruses and human coronaviruses can present similar to influenza (30) . A study of influenza-like illnesses over successive winters in the UK found that 480 of 2226 swabs (21.6%) were positive for respiratory syncytial virus (31) . A smaller study in Scotland found that picornavirus was also an important cause of influenza-like illness (32) . Other studies have also identified rhinovirus (33), adenovirus (33), human corona virus (33) and parainfluenza virus (34) as important causes of influenza-like illness.

Our findings suggest that exposure to influenzalike illnesses may be associated with increased risk of cardiovascular events, hence measures such as influenza vaccination should be supported in line with current recommendations, particularly among patients who are at risk of CVDs.

The definition of influenza varied among studies in the current analysis since both serological tests and clinical assessments were used. We have observed that influenza-like illness defined by clinical features, which may be caused by both influenza and other viral infections such as those highlighted above are associated with an increased risk of MI. This association appears to be absent in influenza cases defined by serology. There are a number of possible explanations that might account for this. The clinical features of influenza may be secondary to other viral infections so using clinical features may include other non-influenza infections. Participants in whom influenza was diagnosed by serology may represent a different biological cohort than those patients in whom influenza diagnosis is based on clinical features. This may be because participants identified from serology may be asymptomatic, have atypical or milder symptoms because of infection with less virulent genotypes of influenza virus while participants who are diagnosed with influenza on clinical grounds might have more severe influenza infections which could manifest cardiovascular complications. Inclusion of asymptomatic cases may lead to a cohort with fewer cardiovascular events and reduced likelihood of detecting differences when compared with control group. Second, the timing of the serology test is important to determine if it is associated with cardiovascular event. Serology tests are able to measure the antibodies that develop in response to influenza virus but this response develops within 2-3 weeks of infection (35) (36) (37) . Once developed, antibodies remain at detectable levels for months (38) , thus making the test reliable in confirming influenza infection exposure. Consequently, if serological testing took place in the acute phase infection, the test result may represent a false negative. The quality of the serology test for influenza may also present a problem as high quality and standardised methods should be used to minimise variability in results. It is notable that two of the studies of serology took place in 1977 and 1981 and it is unclear, if the laboratory tests are as reliable and robust as those having been conducted more recently. Serological tests may detect cross-reactive antibodies generated by previous exposure to antigenically similar viruses leading to false positive results. The current gold standard for laboratory confirmation of influenza virus infection is reverse transcription-polymerase chain reaction or viral culture although this methodology was not used in studies included in the current analysis. It is notable that there are differences between influenza and influenza-like illness. True influenza, which is confirmed by serology, will not include other flu-like mimics unless there is dual infection. However, serologically defined influenza infection will also include asymptomatic cases that may not be clinically relevant and may be missed unless a study defines a cohort and tests all participants regardless of whether they are symptomatic. Influenza-like illness on the other hand may include other viral illnesses as previously described. This population will represent the clinically relevant cohort and may be larger than the true influenza cohort. However, it may be more heterogeneous in clinical features than the influenza cohort because it may include infections with other viruses. The ideal study should actually consider both in parallel. This can be conducted by taking a defined population and testing all participants for influenza and then prospectively collect data on whether participants develop symptoms of influenza. This study will allow understanding of the specificity of the influenza-like illness that is unclear.

While we identified 12 studies of CVDs and patients with influenza and influenza-like illness, and built on existing reviews. This study was the first to quantify the risk, to consider serological diagnosis separately from symptomatic diagnoses and to review the limited evidence for risk of stroke and HF with influenza-like illness. However, many of the studies were of low quality and more than 10-years old, so their findings may not generalise well to current clinical practice and settings.

While we found some evidence to support the role of influenza-like illnesses as a trigger for cardiovascular events the precise mechanism is unclear. It has been suggested that influenza and influenza-like illnesses may increase the risk of acute MI by mechanisms such as: antigenic cross-reactivity; increased proinflammatory and pro-thrombotic cytokines; loss of anti-inflammatory properties of HDL particles; increased trafficking of macrophages into the arterial wall; pronounced expression of inflammatory cytokines by infected monocytes; reduced clotting times and induction of pro-coagulant activity by infected endothelial cells and increased expression of tissue factor (18) . Coagulopathy and inflammation are thought to be key factors (39) . Inflammation is also an important part of the atherosclerotic process and inflammatory cytokines such as TNF-a and IL-6 are increased in the context of studies of influenza in mice (40) . Repeated influenza infection may injure the vascular endothelial cells and initiate the inflammatory response that is required to accelerate and enhance atherosclerosis development (18) . Furthermore, viral infections can trigger the production of inflammatory cytokines, which could destabilise existing vulnerable plaques leading to MI (41) . It is worth noting that included studies were of high risk of bias because of their retrospective nature and study designs, which were case-control or case cross-over. In addition, bias may arise from the variation in the way influenza was diagnosed which ranged from symptoms associated with respiratory infection to diagnoses based on serology tests. The most reliable diagnostic methodology is laboratory serological tests, as other chest infections or atypical respiratory infections may have clinical features consistent with influenza infection. However, even when serological tests were used to ascertain influenza infection, it is possible that patients who did not have serology positive influenza did not have flu and this may account for the dissimilarity between the two large cohorts evaluating public health records and the remaining studies. Furthermore, adjustments for potential confounders are important to reduce risk of bias. Only a limited number of studies in the current review adjusted for baseline variables and there is always the risk of unmeasured confounders.

Reporting bias represents a limitation in some of the studies included in the current review. Data from large databases may fail to capture asymptomatic cases of influenza, which do not present the health services or patients who self medicate and do not seek medical attention. Another limitation relates to the inclusion of older studies that used different diagnostic criteria for MI. The diagnostic criteria for MI in older studies were based mainly on clinical criteria, echocardiography, electrocardiographical changes and possible enzyme rises of creatinine kinase that are not as sensitive as high sensitivity troponin assays used in contemporary practice to detect myonecrosis, which may have resulted in underreporting of incident MI in older studies Further studies should be conducted to evaluate the risk of CVD with influenza. These observational studies should be prospective in design with outcomes linked to a CVD register. Once potential cases of influenza are identified, further laboratory tests should be performed to confirm diagnosis of influenza. In addition, important potential confounders such as smoking, socioeconomic status, underlying chronic respiratory disease and other cardiovascular risk factors need to be accounted for in risk-adjusted models.

In conclusion, there is an apparent association between influenza-like illness and adverse cardiovas-cular events. This association is less clear for serologically defined influenza, which may be a limitation of published data and study designsthere are many biologically plausible mechanisms to explain the relationship. We recommend renewed efforts to apply current clinical guidelines and maximise the uptake of annual influenza immunisation among patients with CVDs, to decrease their risks of MI and stroke.

MAM conceptualised the review. CSK and YKL performed the literature search. CSK and SU screened the search results for relevant studies and extracted the data. CSK, EK and YKL were involved in the data-analysis. CSK drafted the manuscript and all authors contributed in writing of the paper.

Additional Supporting Information may be found in the online version of this article: Table S1 . Risk of bias assessment of included studies. Figure S1 . Flow diagram of study selection. 

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