Influenza, Influenza-like Symptoms and Their Association With Cardiovascular Risks
Influenza, Influenza-like Symptoms and Their Association With Cardiovascular Risks
We identified 12 studies that met the inclusion criteria. Details of the study selection are shown in Figure S1 http://onlinelibrary.wiley.com/store/10.1111/ijcp.12646/asset/supinfo/ijcp12646-sup-0001-Supinfo.doc?v=1&s=ce54872dddd706bb4a2030d12407f23e34e9f331. 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 http://onlinelibrary.wiley.com/store/10.1111/ijcp.12646/asset/supinfo/ijcp12646-sup-0001-Supinfo.doc?v=1&s=ce54872dddd706bb4a2030d12407f23e34e9f331. 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, lung tissue testing and a validated algorithm. Apart from one study where ascertainment of outcome was unclear, all studies reported methods that could reliably identify cardiovascular events. Three studies reported use of adjustments for more than two potential confounders. In terms of risk of bias, one study was classified as low risk of bias and three studies were classified as high risk of bias.
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. The reporting of the follow-up or timing of influenza exposure was variable. Three studies did not report any information on this, 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, one study evaluated ischaemic stroke and one study evaluated HF.
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. 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 = 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 = 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) studies – see Figure 2.
(Enlarge Image)
Figure 1.
Risk of myocardial infarction with influenza based on serology or laboratory tests
(Enlarge Image)
Figure 2.
Risk of myocardial infarction with influenza-like illness
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).
The study by Nicholls et al. was the only study that evaluated the risk of HF with influenza. 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 flu-like illness and risk of ischaemic stroke. 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. 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).
Results
Study Design and Participant Characteristics
We identified 12 studies that met the inclusion criteria. Details of the study selection are shown in Figure S1 http://onlinelibrary.wiley.com/store/10.1111/ijcp.12646/asset/supinfo/ijcp12646-sup-0001-Supinfo.doc?v=1&s=ce54872dddd706bb4a2030d12407f23e34e9f331. 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.
Quality Assessment of Included Studies
The study quality assessment is shown in Table S1 http://onlinelibrary.wiley.com/store/10.1111/ijcp.12646/asset/supinfo/ijcp12646-sup-0001-Supinfo.doc?v=1&s=ce54872dddd706bb4a2030d12407f23e34e9f331. 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, lung tissue testing and a validated algorithm. Apart from one study where ascertainment of outcome was unclear, all studies reported methods that could reliably identify cardiovascular events. Three studies reported use of adjustments for more than two potential confounders. In terms of risk of bias, one study was classified as low risk of bias and three studies were classified as high risk of bias.
Influenza Exposure and Cardiovascular Outcomes
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. The reporting of the follow-up or timing of influenza exposure was variable. Three studies did not report any information on this, 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, one study evaluated ischaemic stroke and one study evaluated HF.
Risk of Myocardial Infarction With Influenza
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. 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 = 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 = 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) studies – see Figure 2.
(Enlarge Image)
Figure 1.
Risk of myocardial infarction with influenza based on serology or laboratory tests
(Enlarge Image)
Figure 2.
Risk of myocardial infarction with influenza-like illness
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).
Risk of HF With Influenza
The study by Nicholls et al. was the only study that evaluated the risk of HF with influenza. 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).
Risk of Stroke With Influenza
The study by Luna et al. evaluated the timing of flu-like illness and risk of ischaemic stroke. 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.
Risk of Cardiovascular Mortality With Influenza
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. 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).