Influenza Causes Deaths From Heart and Respiratory Disease

Collins SD. Excess mortality from causes other than influenza and pneumonia during influenza epidemics. Pub Health Rep 1932 Nov 11;47:2159-2179. Data from 35 cities betweem 1917 and 1929. "A study of excess mortality from all causes during the various respiratory epidemics that have occurred during the past 15 years indicates that in every one the excess mortality from all causes was appreciably higher than the excess mortality credited to influenza and pneumonia. If this situation were true of only one or two of the epidemics, it might be assumed that an unrelated epidemic of some other disease occurred simultaneously with the influenza epidemic; but when every outbreak repeats the phenomenon, it can hardly be concluded that the excess deaths from causes other than influenza and pneumonia are unrelated to the excess deaths from influenza and pneumonia." "In the case of organic heart diseases there was a peak, corresponding in time with the influenza peak, for practically every epidemic... Nephritis and diabetes both had some peaks corresponding in time to the influenza peaks, but they were smaller and less definite than in the case of organic heart diseases. Cerebral hemorrhage showed peaks during some of the epidemics."

Collins - Pub Health Rep 1932 full article / PubMed Central (pdf, 31 pp)

Acute respiratory-tract infections and risk of first-time acute myocardial infarction. CR Meier, SS Jick, LE Derby, C Vasilakis, H Jick. Lancet 1998 May 16;351(9114):1467-1471. 1922 cases and 7649 matched controls. "The odds ratios, adjusted for smoking and body-mass index, for first-time AMI in association with an acute respiratory-tract infection 1-5, 6-10, 11-15, or 16-30 days before the index date (compared with participants who had no such infection during the preceding year) were 3.6 (95% CI 2.2-5.7), 2.3 (1.3-4.2), 1.8 (1.0-3.3), and 1.0 (0.7-1.6); (test for trend p<0.01). The case-crossover analysis showed a relative risk of 2.7 (1.6-4.7) for AMI in relation to an acute respiratory-tract infection in the 10 days before the index date."

Meier - Lancet 1998 abstract / PubMed

Influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies. M Madjid, M Naghavi, S Litovsky, SW Casscells. Circulation 2003 Dec 2;108(22):2730-276. Review. "Whereas the majority of the suspected infectious agents play their atherogenic role by initiating or aggravating a chronic vascular or systemic inflammatory process, influenza may have a rather different effect by triggering destabilization of already present vulnerable plaques." Vaccines and neuraminidase inhibitors could prevent at least 36,450 to 72,900 CVD deaths per year.

Madjid / Circulation 2003 full article

Risk of myocardial infarction and stroke after acute infection or vaccination. L Smeeth, SL Thomas, AJ Hall, R Hubbard, P Farrington, P Vallance. N Engl J Med 2004 Dec 16;351(25):2611-2618. 20,486 persons with a first myocardial infarction and 19,063 persons with a first stroke who received influenza vaccine. "There was no increase in the risk of myocardial infarction or stroke in the period after influenza, tetanus, or pneumococcal vaccination. However, the risks of both events were substantially higher after a diagnosis of systemic respiratory tract infection and were highest during the first three days (incidence ratio for myocardial infarction, 4.95; 95 percent confidence interval, 4.43 to 5.53; incidence ratio for stroke, 3.19; 95 percent confidence interval, 2.81 to 3.62). The risks then gradually fell during the following weeks. The risks were raised significantly but to a lesser degree after a diagnosis of urinary tract infection. The findings for recurrent myocardial infarctions and stroke were similar to those for first events."

Smeeth / N Engl J Med 2004 full article

Influenza and the winter increase in mortality in the United States, 1959-1999. TA Reichert, L Simonsen, A Sharma, SA Pardo, DS Fedson, MA Miller. Am J Epidemiol 2004 Sep 1;160(5):492-502. "The peak months in the ZLS curve for pneumonia and influenza coincided with those for ischemic heart disease 34 of 40 times, for cerebrovascular disease 33 of 40 times, and for diabetes 34 of 40 times. When misaligned, the pneumonia and influenza peak always occurred 1 month later than the peak in other disease mortality." "The magnitude of the seasonal component was highly correlated with traditional measures of excess mortality and was significantly larger in seasons dominated by influenza A(H2N2) and A(H3N2) viruses than in seasons dominated by A(H1N1) or B viruses... These findings suggest that the cause of the winter increase in US mortality is singular and probably influenza. Weather and other factors may determine the timing and modulate the magnitude of the winter-season increase in mortality, but the primary determinant appears to be the influenza virus."

Reichert / Am J Epidemiol 2004 full article

Influenza and its relationship to circulatory disorders. DM Fleming, KW Cross, RS Pannell. Epidemiol Infect 2005 Apr;133(2):255-262. Epidemiol Infect 2005 Apr;133(2):255-262. Data from the Royal College of General Practitioners, England, in winter 1994/1995 to 1999/2000. "The large cross-correlation coefficients of deaths (circulatory and respiratory) with GP respiratory episodes at weekly lags of 0, -1 and 1 were evidence that the deaths and episode distributions were contemporaneous. The ratios of excess circulatory deaths relative to excess respiratory deaths during epidemic periods were 0.74 (age 45–64), 0.72 (65–74) and 0.57 (> or = 75 years). Increased circulatory deaths contemporary with new incident cases of respiratory episodes but with no concomitant increase in admissions suggests rapid death during the acute phase of illness." Fig. 2 shows that during flu peaks, circulatory deaths exceeded GP visits, and were also followed by a deficit of circulatory admissions. "Many of the deaths must, therefore, be occurring in the community suggesting rapid progress of the illness or sudden death. This would be consistent with the many reports of ECG abnormalities associated with influenza. Sudden death from dysrhythmia is rarely diagnosed and is not evident on autopsy findings." They concluded that increased circulatory mortality due to influenza was about 60% that of excess respiratory mortality.

Fleming - Epidemiol Infect 2005 full article / PubMed Central (pdf, 8 pp)

Influenza epidemics and acute respiratory disease activity are associated with a surge in autopsy-confirmed coronary heart disease death: results from 8 years of autopsies in 34,892 subjects. M Madjid, CC Miller, VV Zarubaev, IG Marinich, OI Kiselev, YV Lobzin, AE Filippov, SW Casscells 3rd. Eur Heart J 2007 May;28(10):1205-1210. Autopsies were conducted from 1993 to 2000 in St Petersburg, Russia, where autopsy rates were high and flu vaccination was rare. 11,892 subjects died of AMI and 23 000 subjects died of chronic IHD. "In every year, a peak of AMI and chronic IHD deaths were present and coincided with the influenza epidemic and peak ARD activity. A similar pattern was seen for each subgroup of men, women, subjects 50 years or older, and subjects 70 years or older. When comparing the average influenza epidemic weeks to average off-season weeks, the odds for AMI and chronic IHD death increased by 1.30 (95% confidence interval (CI): 1.08-1.56) and 1.10 (95% CI: 0.97-1.26), respectively." Deaths from AMI peaked at the end of winter, while deaths from chronic IHD peaked at the beginning of spring. They also note that "The reported death rate attributed to influenza is mainly based on the study of death certificates which generally underestimate deaths due to influenza and often misclassify the clinical outcomes as well... From our own observational study, and a closer examination of published trials, we estimated that influenza causes up to 92 000 deaths per year in US only through triggering of fatal myocardial infarctions."

Madjid / Eur Heart J 2007 full article

Influenza virus infection and risk of acute myocardial infarction. XR Guan, X Li, XM Xin, LX Jiang, LY Cui, LF Wang, HY Li. Inflammation 2008 Aug;31(4):266-272. "Fasting blood sample was obtained to measure IgG antibodies to influenza virus A(IV-A), influenza virus B(IV-B), cytomegalovirus (CMV), herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2), adenovirus (ADV), rubella virus (RV) and Chlamydia pneumoniae (CP) and measure the level of some biochemistry markers. Compared to controls, cases were more likely to have positive IgG antibodies to IV-A and IV-B (IV-A: OR, 3.3; 95%CI, 1.5 to 7.4; IV-B: OR, 17.2; 95%CI, 7.7 to 38.0). After adjustment for potential confounding variables, the risk of AMI was still associated with the presence of IgG antibodies to IV-A (adjusted OR, 7.5; 95%CI, 1.3 to 43.0) and IV-B (adjusted OR, 27.3; 95%CI, 6.6 to 113.8)."

Guan - Inflammation 2008 abstract / PubMed

Influenza-like illness in acute myocardial infarction patients during the winter wave of the influenza A H1N1 pandemic in London: a case-control study.C Warren-Gash, AM Geretti, G Hamilton, RD Rakhit, L Smeeth, AC Hayward. BMJ Open 2013 May 2;3(5) pii: e002604. 70 acute myocardial infarction cases and 64 acute surgical controls. "29 of 134 (21.6%) participants reported respiratory illness within the last month, of whom 13 (9.7%) had illnesses meeting ILI criteria. The most frequently reported category for timing of respiratory symptom onset was 8-14 days before admission (31% of illnesses). Cases were more likely than controls to report ILI-adjusted OR 3.17 (95% CI 0.61 to 16.47)-as well as other key respiratory symptoms, and were less likely to have received influenza vaccination-adjusted OR 0.46 (95% CI 0.19 to 1.12)-although the differences were not statistically significant. No swabs were positive for influenza virus."

Warren-Gash - BMJ Open 2013 full article / PubMed Central
Warren-Gash / BMJ Open 2013 full article

Association Between Influenza Vaccination and Cardiovascular Outcomes in High-Risk Patients A Meta-analysis. JA Udell, R Zawi, DL Bhatt, M Keshtkar-Jahromi, F Gaughran, A Phrommintikul, A Ciszewski, H Vakili, EB Hoffman, ME. Farkouh, CP Cannon. JAMA 2013 Oct 23/30;310(16):1711-1720. 6735 participants in 5 randomized clinical trials. "Influenza vaccine was associated with a lower risk of composite cardiovascular events (2.9% vs 4.7%; RR, 0.64 [95% CI, 0.48-0.86], P = .003) in published trials. A treatment interaction was detected between patients with (RR, 0.45 [95% CI, 0.32-0.63]) and without (RR, 0.94 [95% CI, 0.55-1.61]) recent ACS (P for interaction = .02). Results were similar with the addition of unpublished data."

Udell / JAMA 2013 full article

Influenza and respiratory syncytial virus are the major respiratory viruses detected from prospective testing of pediatric and adult coronial autopsies.DJ Speers, DM Moss, C Minney-Smith, A Levy, DW Smith. Influenza Other Respi Viruses 2013 Nov;7(6):1113-1121. 1611 coronial cases where the death was either unknown or infection was suspected, from July 2007 to June 2011. "Influenza virus was the commonest respiratory virus (50 cases, 3%), followed by respiratory syncytial virus (RSV) (30 cases, 2%)... influenza A and RSV predominated in those over 60 years, but coinfection was uncommon. Almost all influenza cases occurred when influenza was widely circulating in the community but few were diagnosed pre-mortem. Influenza and RSV detection was associated with bronchitis or bronchiolitis in 7 (9%) of the 80 cases and caused pneumonia in 14 (08%) deaths overall."

Speers - Influenza Other Respi Viruses 2013 abstract / PubMed

Influenza Transmission

An outbreak of influenza aboard a commercial airliner. MR Moser, TR Bender, HS Margolis, GR Noble, AP Kendal, DG Ritter. Am J Epidemiol 1979 Jul;110(1):1-6. "A jet airliner with 54 persons aboard was delayed on the ground for three hours because of engine failure during a takeoff attempt. Most passengers stayed on the airplane during the delay. Within 72 hours, 72 per cent of the passengers became ill with symptoms of cough, fever, fatigue, headache, sore throat and myalgia. One passenger, the apparent index case, was ill on the airplane, and the clinical attack rate among the others varied with the amount of time spent aboard. Virus antigenically similar to A/Texas/1/77(H3N2) was isolated from 8 of 31 passengers cultured, and 20 of 22 ill persons tested had serologic evidence of infection with this virus. The airplane ventilation system was inoperative during the delay and this may account for the high attack rate."

Moser - Am J Epidemiol 1979 abstract / PubMed

Influenza virus transmission is dependent on relative humidity and temperature. AC Lowen, S Mubareka, J Steel, P Palese. PLoS Pathog 2007 Oct 19;3(10):1470-1476. In Guinea pigs. "We found that low relative humidities of 20%–35% were most favorable, while transmission was completely blocked at a high relative humidity of 80%. Furthermore, when guinea pigs were kept at 5 C, transmission occurred with greater frequency than at 20 C, while at 30 C, no transmission was detected. Our data implicate low relative humidities produced by indoor heating and cold temperatures as features of winter that favor influenza virus spread."

Lowen - PLoS Pathog 2007 full article / PubMed Central
Lowen / PLoS Pathog 2007 full article

Inactivation of influenza A viruses in the environment and modes of transmission: a critical review. TP Weber, NI Stilianakis. J Infect 2008 Nov;57(5):361-373. "[O]n inanimate surfaces and in aerosols daily inactivation rates are in the order of 1-10(2), on hands in the order of 10(3). Influenza virus can survive in aerosols for several hours, on hands for a few minutes. Nasal infectious dose of influenza A is several orders of magnitude larger than airborne infectious dose."

Weber - J Infect 2008 abstract / PubMed Central

Measurement of airborne influenza virus in a hospital emergency department. FM Blachere, WG Lindsley, TA Pearce, SE Anderson, M Fisher, R Khakoo, BJ Meade, O Lander, S Davis, RE Thewlis, I Celik, BT Chen, DH Beezhold. Clin Infect Dis 2009 Feb 15;48(4):438-440. "Forty-six percent of the influenza virus particles were found in the first stage of the samplers, which collected particles with a diameter >4 m. However, 49% of the isolates were collected in the second stage, which collects particles with a diameter of 1–4-m, and 4% were collected on the back-up filter, which collects particles with a diameter <1 m. These findings indicate that >50% of the total viral particles were found in the respiratory aerosol fraction."

Blachere / Clin Infect Dis 2009 full article

Absolute humidity and the seasonal onset of influenza in the continental United States. J Shaman, VE Pitzer, C Viboud, BT Grenfell, M Lipsitch. PLoS Biol 2010 Feb 23;8(2):e1000316. "[T]he onset of increased wintertime influenza-related mortality in the United States is associated with anomalously low absolute humidity levels during the prior weeks. We then use an epidemiological model, in which observed absolute humidity conditions temper influenza transmission rates, to successfully simulate the seasonal cycle of observed influenza-related mortality."

Shaman - PLoS Biol 2010 full article / PubMed Central
Shaman / PLoS Biol 2010 full article

Distribution of airborne influenza virus and respiratory syncytial virus in an urgent care medical clinic. WG Lindsley, FM Blachere, KA Davis, TA Pearce, MA Fisher, R Khakoo, SM Davis, ME Rogers, RE Thewlis, JA Posada, JB Redrow, IB Celik, BT Chen, DH Beezhold. Clin Infect Dis 2010 Mar 1;50(5):693-698. "Seventeen percent of the stationary samplers contained influenza A RNA, 1% contained influenza B RNA, and 32% contained RSV RNA. Nineteen percent of the personal samplers contained influenza A RNA, none contained influenza B RNA, and 38% contained RSV RNA. The number of samplers containing influenza RNA correlated well with the number and location of patients with influenza (r= 0.77). Forty-two percent of the influenza A RNA was in particles < or = 4.1 microm in aerodynamic diameter, and 9% of the RSV RNA was in particles < or = 4.1 microm."

Lindsley / Clin Infect Dis 2010 full article

Concentrations and size distributions of airborne influenza A viruses measured indoors at a health centre, a day-care centre and on aeroplanes. W Yang, S Elankumaran, LC Marr. J R Soc Interface 2011 Aug 7;8(61):1176-1184. "Half of the 16 samples were positive, and their total virus concentrations ranged from 5800 to 37,000 genome copies m(-3). On average, 64 per cent of the viral genome copies were associated with fine particles smaller than 2.5 m, which can remain suspended for hours. Modelling of virus concentrations indoors suggested a source strength of 1.61.210(5) genome copies m(-3) air h(-1) and a deposition flux onto surfaces of 137 genome copies m(-2) h(-1) by Brownian motion. Over 1 hour, the inhalation dose was estimated to be 3018 median tissue culture infectious dose (TCID50), adequate to induce infection. These results provide quantitative support for the idea that the aerosol route could be an important mode of influenza transmission." Sampling was between 10 December 2009 and 22 April 2010.

Yang - J R Soc Interface 2011 full article / PubMed Central
Yang - J R Soc Interface 2011 full article

Environmental Predictors of Seasonal Influenza Epidemics across Temperate and Tropical Climates. JD Tamerius, J Shaman, WJ Alonso, K Bloom-Feshbach, CK Uejio, A Comrie, C Viboud. PLoS Pathog 2013;9(3):e1003194. 78 worldwide study sites. "We substantiated that there are two types of environmental conditions associated with seasonal influenza epidemics: 'cold-dry' and 'humid-rainy'. For sites where monthly average specific humidity or temperature decreases below thresholds of approximately 11–12 g/kg and 18–21C during the year, influenza activity peaks during the cold-dry season (i.e., winter) when specific humidity and temperature are at minimal levels. For sites where specific humidity and temperature do not decrease below these thresholds, seasonal influenza activity is more likely to peak in months when average precipitation totals are maximal and greater than 150 mm per month."

Tamerius / PLoS Pathog 2013 full article

Influenza Virus Aerosols in Human Exhaled Breath: Particle Size, Culturability, and Effect of Surgical Masks. DK Milton, MP Fabian, BJ Cowling, ML Grantham, JJ McDevitt. PLoS Pathog 2013;9(3):e1003205. 37 subjects. "We found that total viral copies detected by molecular methods were 8.8 times more numerous in fine (≤5 m) than in coarse (>5 m) aerosol particles and that the fine particles from cases with the highest total number of viral RNA copies contained infectious virus. Surgical masks reduced the overall number of RNA copies by 3.4 fold." "Self-reported tachypnea, breathing difficulty, smoking, and lymphadenopathy were not associated with significant shifts in exhaled copy numbers... In the coarse fraction, each additional day after onset was associated with a 6.0 fold drop in the number of virus copies detected (95% CI 1.7 to 21 fold). Fine particles also declined with time, each additional day after onset was associated with a 2.4 fold drop in the number of copies detected (95% CI 1.1 to 5.1 fold)."

Milton / PLoS Pathog 2013 full article

Aerosol transmission is an important mode of influenza A virus spread. BJ Cowling, DK Ip, VJ Fang, P Suntarattiwong, SJ Olsen, J Levy, TM Uyeki, GM Leung, JS Malik Peiris, T Chotpitayasunondh, H Nishiura, J Mark Simmerman. Nat Commun 2013;4:1935. "Here we apply a mathematical model to data from randomized controlled trials of hand hygiene and surgical face masks in Hong Kong and Bangkok households. In these particular environments, inferences on the relative importance of modes of transmission are facilitated by information on the timing of secondary infections and apparent differences in clinical presentation of secondary infections resulting from aerosol transmission. We find that aerosol transmission accounts for approximately half of all transmission events."

Cowling / Nat Commun 2013 full article

Roles of humidity and temperature in shaping influenza seasonality. AC Lowen, J Steel. J Virol 2014;88(14):7692-7695. Review.

Lowen / J Virol 2014 full article

The Contribution of Social Behaviour to the Transmission of Influenza A in a Human Population. AJ Kucharski, KO Kwok, VWI Wei, BJ Cowling, JM Read, J Lessler, DA Cummings, S Riley. PLoS Pathog 2014;10(6): e1004206. "Fitting the models to serologically confirmed infection data from the 2009 Hong Kong influenza A/H1N1p pandemic, we found that an individual's risk of infection was influenced strongly by the average reported social mixing behaviour of their age group, rather than by their personal reported contacts. We also identified the resolution of social mixing that shaped transmission: epidemic dynamics were driven by intense contacts between children, a post-childhood drop in risky contacts and a subsequent rise in contacts for individuals aged 35–50."

Kucharski / PLoS Pathog 2014 full article

Influenza and Immunity

Insights into the interaction between influenza virus and pneumococcus. JA McCullers. Clin Microbiol Rev 2006 Jul;19(3):571-582. Review. Influenza A and B viruses both predispose to bacterial infections, particularly S. pneumoniae and S. aureus.

McCullers - Clin Microbiol Rev 2006 full article / PubMed Central
McCullers / Clin Microbiol Rev 2006 full article

Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. K Sun, DW Metzger. Nat Med 2008 May;14(5):558-564. "We now report that pulmonary interferon-gamma (IFN-gamma) produced during T cell responses to influenza infection in mice inhibits initial bacterial clearance from the lung by alveolar macrophages. This suppression of phagocytosis correlates with lung IFN-gamma abundance, but not viral burden, and leads to enhanced susceptibility to secondary pneumococcal infection, which can be prevented by IFN-gamma neutralization after influenza infection. Direct inoculation of IFN-gamma can mimic influenza infection and downregulate the expression of the class A scavenger receptor MARCO on alveolar macrophages."

Sun - Nat Med 2008 abstract / PubMed

Buying time-the immune system determinants of the incubation period to respiratory viruses. T Hermesh, B Moltedo, CB Lpez, TM Moran. Viruses 2010 Nov;2(11):2541-2558. "Here we review studies of the interaction between human pathogenic respiratory RNA viruses and the host with a particular emphasis on the mechanisms used by viruses to inhibit immunity. We discuss the concept of the "stealth phase", defined as the time between infection and the earliest detectable inflammatory response. We propose that the "stealth phase" phenomenon is primarily responsible for the suppression of symptoms during the incubation period and results from viral antagonism that inhibits major pathways of the innate immune system allowing an extended time of unhindered virus replication."

Hermesh - Viruses 2010 full article / PubMed Central

Initial infectious dose dictates the innate, adaptive, and memory responses to influenza in the respiratory tract. I Marois, A Cloutier, Garneau, MV Richter. J Leukoc Biol 2012 Jul;92(1):107-121. "Our results demonstrated that the initial infectious dose significantly affects the gene expression of antiviral (IFN-β) and inflammatory (TNF-α, IL-6, IL-1β) cytokines and of enzymes involved in nitrosative/oxidative stress (iNOS, HO-1, NQO1) early in the response to influenza. This response correlated with significantly increased recruitment of innate immune cells into the lungs of infected mice. We showed that this response also alters the subsequent accumulation of activated IFN-γ(+) CD44(hi) CD62L(lo) influenza-specific CD8(+) T cells into the lungs of infected mice through increased T cell-recruiting chemokine gene expression (CCL3, CCL4, CCL5, CXCL10). Furthermore, we demonstrated that the initial infectious dose determines the generation and the distribution of memory CD8(+) T cell subsets without affecting trafficking mechanisms. This impacted on immune protection against heterologous infection. Lastly, we showed that the effects on innate and adaptive immunity were not dependent on influenza strain or on the genetic background of the host."

Marois - J Leukoc Biol 2012 abstract / PubMed

Innate immune response of human alveolar macrophages during influenza A infection. J Wang, MP Nikrad, EA Travanty, B Zhou, T Phang, B Gao, T Alford, Y Ito, P Nahreini, K Hartshorn, D Wentworth, CA Dinarello, RJ Mason. PLoS One 2012;7(3):e29879. H1N1 influenza virus PR/8. Retinoic acid-induced gene-1 (RIG-I) and interferon (IFN) signaling were dominant at 4 hours post-infection, whereas homeostasis-related pathways such as IL-10 and IL-6 were activated at 24 hpi. "In addition to IFN related genes, PR/8 significantly increased the expression of many cytokine genes and cytokine-regulated genes. These included the proinflammatory cytokines TNF-α (7.3-fold at 4 hpi and 25-fold at 24 hpi), IL-1α (6.9-fold at 24 hpi), and IL-1β (2.3-fold at 4 hpi and 16.3-fold at 24 hpi)... CCL5 was the most increased CC chemokine (232-fold at 4 hpi, 234-fold at 24 hpi)... PR/8 also upregulated expression of IL-6 (36.9-fold at 4 hpi and 66.6-fold at 24 hpi)."

Wang - PLoS One 2012 full article / PubMed Central
Wang / PLoS One 2012 full article

A distinct influenza infection signature in the blood transcriptome of patients with severe community-acquired pneumonia. GP Parnell, AS McLean, DR Booth, NJ Armstrong, M Nalos, SJ Huang, J Manak, W Tang, OY Tam, S Chan, BM Tang. Crit Care 2012 Aug 16;16(4):R157. 12 cases with noninfective systemic inflammatory response syndrome (SIRS), 8 cases of PCR-confirmed influenza A H1N1 2009 pneumonia, 16 with bacterial pneumonia, 3 with positive pathology for both, and 18 healthy volunteers. "The gene-expression profile of H1N1 influenza A pneumonia was distinctly different from those of bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene-expression profile is characterized by upregulation of genes from cell-cycle regulation, apoptosis, and DNA-damage-response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene-expression profile of influenza infection persisted through 5 days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection in whom bacterial co-infection subsequently developed, the influenza gene-expression signature remained unaltered, despite the presence of a superimposed bacterial infection." Genes affecting cell cycle were the most upregulated by H1N1, and interleukins "were heavily overrepresented in the downregulated gene list," suggesting significant immunosuppression. A set of 29 genes was able to distinguish influenza.

Parnell / Crit Care 2012 full article

Kinetics of Coinfection with Influenza A Virus and Streptococcus pneumoniae. AM Smith, FR Adler, RM Ribeiro, RN Gutenkunst, JL McAuley, JA McCullers, AS Perelson. PLoS Pathog 2013;9(3): e1003238. In mice. "We find that influenza viral titers increase when Streptococcus pneumoniae is present and that the bacteria establish and grow rapidly when influenza is present. Our model and analyses suggest that the influenza infection reduces the bacterial clearance ability of alveolar macrophages and that the subsequent S. pneumoniae infection enhances viral release from infected cells."

Smith / PLoS Pathog 2013 full article

Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections. JM O'Bryan, M Woda, M Co, A Mathew, AL Rothman. Immun Ageing 2013 Aug 26;10(1):37. 10 healthy subjects, plus 5 long term. "Our finding that TL in CD4+ T cells specific for the non-recurring acute virus infection, VACV, was longer than TL in T cells specific for the acutely infecting but recurring exposure virus, IAV, supports our initial model in which recurring antigen exposures drive a more rapid TL decay with age. A caveat to this interpretation is that each IAV infection may involve some new epitopes that activate nave T cells (with longer TL)."

O'Bryan / Immun Ageing 2013 full article

Cytokine responses in patients with mild or severe influenza A(H1N1)pdm09. A Bradley-Stewart, L Jolly, W Adamson, R Gunson, C Frew-Gillespie, K Templeton, C Aitken, W Carman, S Cameron, C McSharry. J Clin Virol 2013 Sep;58(1):100-107. Plasma concentrations in patients with severe and mild influenza A(H1N1)pdm09 virus infection, rhinovirus infection and healthy volunteers. "The majority of cytokines measured were elevated in patients with viral respiratory infections compared to the healthy controls. Concentrations of IL-6, IL-10, IL-15, IP-10, IL-2R, HGF, ST2 and MIG were significantly higher (p<0.05) and EGF significantly lower (p=0.0001) in patients with severe influenza A(H1N1)pdm09 virus infection compared to those with mild influenza A(H1N1)pdm09 virus and rhinovirus infection."

Bradley-Stewart - J Clin Virol 2013 abstract / PubMed

A host-based rt-PCR gene expression signature to identify acute respiratory viral infection. AK Zaas, T Burke, M Chen, M McClain, B Nicholson, T Veldman, EL Tsalik, V Fowler, EP Rivers, R Otero, SF Kingsmore, D Voora, J Lucas, AO Hero, L Carin, CW Woods, GS Ginsburg. Sci Transl Med 2013 Sep 18;5(203):203ra126. In 102 subjects and 41 healthy volunteers, "The selected gene set on the RT-PCR TLDA assay classified participants with experimentally induced influenza H3N2 and H1N1 infection with 100 and 87% accuracy, respectively." In 102 individuals arriving at an emergency department: "The sensitivity of the RT-PCR test was 89% [95% confidence interval (CI), 72 to 98%], and the specificity was 94% (95% CI, 86 to 99%)."

Zaas - Sci Transl Med 2013 abstract / PubMed

CMV and Influenza

Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence. P Trzonkowski, J Myśliwska, E Szmit, J Wieckiewicz, K Lukaszuk, LB Brydak, M Machała, A Myśliwski. Vaccine 2003 Sep 8;21(25-26):3826-3836. "Non-responders of both ages we characterised by higher levels of anti-CMV IgG and higher percentages of CD57+CD28- lymphocytes (known to be associated with CMV carrier status) together with increased concentrations of TNFalpha and IL6 and decreased levels of cortisol."

Trzonkowski - Vaccine 2003 abstract / PubMed

Immunosenescence and vaccine failure in the elderly. B Grubeck-Loebenstein, S Della Bella, AM Iorio, JP Michel, G Pawelec, R Solana. Aging Clin Exp Res 2009 Jun;21(3):201-209. From a meeting of experts in immunology and gerontology in Paris, France, in April 2008. "In particular, an accumulation of late differentiated effector T cells, commonly associated with cytomegalovirus infection, contributes to a decline in the capacity of the adaptive immune system to respond to novel antigens."

Della Bella - Aging Clin Exp Res 2009 abstract / PubMed

Perforin and IL-2 upregulation define qualitative differences among highly functional virus-specific human CD8 T cells. G Makedonas, N Hutnick, D Haney, AC Amick, J Gardner, G Cosma, AR Hersperger, D Dolfi, EJ Wherry, G Ferrari, MR Betts. PLoS Pathog 2010 Mar 5;6(3):e1000798. 23 normal donors. "While EBV and flu-specific CD8(+) T cells rarely upregulate perforin, CMV-specific cells often do and Ad stimulates an exceptionally strong perforin response... Taken together, these results suggest that there are substantially different CD8+ T cell functional profiles against CMV, EBV, Ad, and flu, and that no single function (or pair of functions) likely defines a universal correlate of immune protection for all of these viruses."

Makedonas - PLoS Pathog 2010 full article / PubMed Central
Makedonas / PLoS Pathog 2010 full article

Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination. E Derhovanessian, H Theeten, K Hhnel, P Van Damme, N Cools, G Pawelec. Vaccine 2013 Jan 11;31(4):685-690. 54 subjects of different ages. "CMV-seropositivity was significantly associated with a lower response rate to the vaccine in people over but not below 60yr of age. Unlike reported data, late-differentiated (CD45RA+CCR7-CD27-CD28-) CD4+, but not CD8+ T-cells associated with a poorer vaccine response."

Derhovanessian - Vaccine 2012 abstract / PubMed

Antiviral therapy can reverse the development of immune senescence in elderly mice with latent cytomegalovirus infection. M Beswick, A Pachnio, SN Lauder, C Sweet, PA Moss. J Virol 2013 Jan;87(2):779-789. "Treatment reduced the magnitude of the MCMV-specific CD8(+) T-lymphocyte response by 80%, and the residual MCMV tetramer-specific lymphocytes exhibited a less differentiated phenotype. In addition, latent MCMV infection suppressed the proportion of nave CD8(+) T cells by 60% compared to antiviral-treated mice or MCMV-negative animals. Furthermore, treatment led to a reduction in influenza A viral loads following a challenge in elderly MCMV-infected animals and also reduced the differentiation of influenza virus-specific cytotoxic lymphocytes."

Beswick - J Virol 2013 abstract / PubMed

Impact of human cytomegalovirus (CMV) infection on immune response to pandemic 2009 H1N1 influenza vaccine in healthy adults. A Wald, S Selke, A Magaret, M Boeckh. J Med Virol 2013 Sep;85(9):1557-1560. 52 persons aged 18-64 and 55 aged 65 and older. "Among the younger group, 33% had CMV antibody compared with 62% among the older group. No differences by CMV seropositivity in the proportion of participants achieving a seroprotective titer 21 days following the second immunization were noted. However, the geometric mean titer in hemagglutination inhibition assay was significantly higher among CMV seronegative younger participants compared with CMV seropositive younger participants (385 vs. 142, P = 0.013). In contrast, among the older group, CMV serostatus was not associated with differential antibody titers (53 vs. 63, P = 0.75)."

Wald - J Med Virol 2013 abstract / PubMed

Influenza and Class

Disparities in the Severity of Influenza Illness: A Descriptive Study of Hospitalized and Nonhospitalized Novel H1N1 Influenza-PositivePatients in New York City: 2009-2010 Influenza Season. NS Levy, TQ Nguyen, E Westheimer, M Layton. J Public Health Manag Pract 2013 Jan;19(1):16-24. 128 hospitalized patients with laboratory-confirmed 2009 H1N1 influenza versus 337 non-hospitalized patients with laboratory-confirmed influenza A. "We identified a gradient in the odds of hospitalization for 2009 H1N1 influenza by education level among adults. This association could not be entirely explained by access to care and underlying risk factors. An inverse association between odds of hospitalization and neighborhood poverty was also identified among adults and children."

Levy - J Public Health Manag Pract 2013 abstract / PubMed

Antibiotics and Flu

Clarithromycin inhibits type A seasonal influenza virus infection in human airway epithelial cells. M Yamaya, K Shinya, Y Hatachi, H Kubo, M Asada, H Yasuda, H Nishimura, R Nagatomi. J Pharmacol Exp Ther 2010 Apr;333(1):81-90. "Human influenza viruses attach to sialic acid with an α2,6linkage (SAα2,6Gal) on the airway epithelial cells, and the entry of the viruses into the cells and uncoating of the viruses require low pH of endosomes." In cultured human tracheal epithelial cells infected with type A influenza virus (H3N2), "Influenza virus infection increased viral titers and the content of cytokines, including interleukin (IL)-1β and IL-6, in supernatant fluids, and viral RNA in the cells. Clarithromycin reduced viral titers and the content of cytokines in supernatant fluids, viral RNA in the cells, and the susceptibility to virus infection. Clarithromycin reduced the expression of SAα2,6Gal, a receptor for human influenza virus, on the mucosal surface of human tracheae, and the number and fluorescence intensity of acidic endosomes in the cells from which viral ribonucleoproteins enter into the cytoplasm. Furthermore, clarithromycin reduced nuclear factor-κB (NF-κB) proteins, including p50 and p65, in the nuclear extracts."

Yamaya / J Pharmacol Exp Ther 2010 full article

CDC Estimate of Influenza Deaths

The Centers for Disease Control estimates that influenza causes ~3,000 to ~49,000 deaths per season, depending on the prevailing strain. About 90% of influenza associated deaths occur among adults 65 years and older. "CDC estimated that only 8.5% of all pneumonia and influenza deaths and only 2.1% of all respiratory and circulatory deaths were influenza-related." (Estimating Seasonal Influenza-Associated Deaths in the United States: CDC Study Confirms Variability of Flu Questions and Answers. Page last updated: June 24, 2011.)

Estimating Seasonal Influenza-Associated Deaths / CDC

Comment: The Ridiculous Disparity Between Influenza Deaths and EPA's Purported Deaths from Air Pollution

What needs to be explained is how such a supposedly tiny proportion of deaths correlates with such large changes in death rates that they're clearly visible even in simple analyses from the 1930s. As noted in 1932: "If this situation were true of only one or two of the epidemics, it might be assumed that an unrelated epidemic of some other disease occurred simultaneously with the influenza epidemic; but when every outbreak repeats the phenomenon, it can hardly be concluded that the excess deaths from causes other than influenza and pneumonia are unrelated to the excess deaths from influenza and pneumonia." And in 2004: "The peak months in the ZLS curve for pneumonia and influenza coincided with those for ischemic heart disease 34 of 40 times, for cerebrovascular disease 33 of 40 times, and for diabetes 34 of 40 times. When misaligned, the pneumonia and influenza peak always occurred 1 month later than the peak in other disease mortality."

Yet in contrast to the paltry 63,000 deaths per season attributed to influenza in 2006 by the CDC, the Environmental Protection Agency pretends that a humongous 130,000 to 340,000 deaths were due to PM2.5 and ozone (Estimating the National Public Health Burden Associated with Exposure to Ambient PM2.5 and Ozone. N Fann, AD Lamson, SC Anenberg, K Wesson, D Risley, BJ Hubbell. Risk Analysis 2012 Jan;32(1):81–95.) This is despite the fact that no study of air pollution can demonstrate a direct and straightforward correlation of air pollution with mortality, as those of influenza and mortality do so reliably. For air pollution, the data must be massaged and cooked and finally expressed as a ratio, which is then applied to nationwide pollution measurements. And the ratios they used are based on two cohort studies, whose politically-connected authors, namely Jonathan M. Samet and the American Cancer Society, have a consistent track record of committing scientific fraud by downplaying or outright ignoring the role of infection.

Fann - Risk Analysis 2012 full article / CDC

(NMMAPS) "Smooth functions of calendar time (natural cubic splines) were used to adjust for seasonality and long-term trends, such as influenza epidemics."(Ozone and Short-term Mortality in 95 US Urban Communities, 1987-2000. ML Bell, A McDermott, SL Zeger, J Samet, F Dominici. JAMA 2004; 292(19):2372–2378.) And that is the only mention of influenza. Those adjustments are clearly inadequate, probably due to the known undercount of influenza deaths. And it's not possible to create an accurate risk assessment when the largest risks are not accurately identified in the first place.

Bell - JAMA 2004 full article / PubMed Central

(CPS-II) "They obtained death certificates for participants who were known to have died and compiled cause-of-death information. Causes of death analyzed in this study fall into these categories: all causes, cardiopulmonary disease, ischemic heart disease, lung cancer, and all other causes." But there is no mention of influenza here. (Extended follow-up and spatial analysis of the American Cancer Society study linking particulate air pollution and mortality. D Krewski, M Jerrett, RT Burnett, R Ma, E Hughes, Y Shi, C Turner, CA Pope, G Thurston, EE Calle, MJ Thun. HEI Research Report, 140. Health Effects Institute, 2009.) The Health Effects Institute gets about half its funding from the US EPA, and shakes down the automotive industry for most of the rest.

Krewski / Health Effects Institute 2009 landing page

(CPS-II) "Death certificates or codes for cause of death were obtained for >98% of known deaths." (Cardiovascular Mortality and Long-Term Exposure to Particulate Air Pollution. CA Pope, RT Burnett, GD Thurston, MJ Thun, EE Calle, D Krewski, JJ Godleski. Am J Respir Crit Care Med 1995 Mar;151(3 Pt 1):669-674.) The very same death certificates which are known to undercount influenza deaths.

Pope / Am J Respir Crit Care Med 1995 full article

(CPS-II) No mention of influenza here. "Death certificates or codes for cause of death were obtained for more than 98% of all known deaths." (Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution.CA Pope 3rd, RT Burnett, MJ Thun, EE Calle, D Krewski, K Ito, GD Thurston. JAMA 2002 Mar 6;287(9):1132-1141.) The very same death certificates which are known to undercount influenza deaths.

Pope / JAMA 2002 full article

(Re-analysis of NMMAPS data) Temperature, Not Fine Particulate Matter (PM2.5), is Causally Associated with Short-Term Acute Daily Mortality Rates: Results from One Hundred United States Cities. T Cox, D Popken, PF Ricci. Dose Response 2013;11(3): 319–343. "Table 3. Granger tests show no significant causal association between PM2.5 and mortality rates in daily time series." And: "Table 4. Granger tests strongly reject the null hypothesis of no significant causal association between temperature (tmin) and mortality rates in daily time series." "The contrast between our negative findings and conclusions from previous analyses of the NMMAPS data set, and other data sets, requires some explanation. We propose that the following factors may contribute to the differences in conclusions... Splines provide some smoothing, and eliminate more confounding than a linear model, but may leave some residual confounding, especially if the spline is relatively stiff... But the methodological point is that, if a clear, robust causal relation exists – one that does not depend on details of modeling choices – then it is puzzling that it is not more apparent when model-free methods and other analyses are used to look for it in this large data set. This may add new weight to previously expressed concerns... that the usual current approaches to analyzing time series data on exposures and mortality rates may be identifying associations that do not necessarily reflect reliable causal relations."

Cox - Dose Response 2013 full article / PubMed Central

And the causal factor that the PM2.5 demagogues are ignoring is the influenza virus: "...the cause of the winter increase in US mortality is singular and probably influenza. Weather and other factors may determine the timing and modulate the magnitude of the winter-season increase in mortality, but the primary determinant appears to be the influenza virus." (Reichert 2004; also Shaman 2010)

See Also:

Geographic Spread of Influenza as Assessed by State and Territorial Epidemiologists. Pattern of flu activity shifts state by state, from no activity to sporadic, local, and regional to widespread, and then back again. (Weekly US Map: Influenza Summary Update. Centers for Disease Control and Prevention.)

Weekly US Map: Influenza Summary Update / CDC
Weekly Surveillance Reports / CDCCMV & other infections cause heart disease

CMV Impairs Immunity
The Surgeon General Lies That Smoking Causes Heart Disease
The Lie That Secondhand Smoke Causes Heart Disease
Chlamydia pneumoniae causes heart disease

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cast 06-29-14