Primecuts – This Week In The Journals

November 7, 2011

By Jessica Taff, MD

Faculty Peer Reviewed

The New York City Marathon this past weekend marked a yearly event in the city’s lifecycle. As the leaves fall and a November chill fills the air, the race reminds us of the importance of physical activity to our health maintenance. And just when we thought it was too late to reactivate those new year’s resolutions, we were gifted with an extra hour from the daylight savings gods.

In line with this reflection on health prevention and health maintenance, The Lancet Infectious Diseases has published a meta-analysis of the efficacy and effectiveness of the influenza vaccine.[1]. So if you are still vacillating whether or not it is worthwhile get your seasonal flu shot, look no further than this article for a bit more guidance. Currently, the Advisory Committee on Immunization Practices recommends yearly vaccination with the trivalent inactivated vaccine (TIV) for all individuals older than 6 months, or the live attenuated influenza vaccine (LAIV) for healthy non-pregnant people ages 2-49 years.ii However, this study shows some gaps in evidence supporting these recommendations. Eligible articles published between 1967 and 2011 evaluated both the relative risk reduction of circulating influenza viruses during individual flu seasons (efficacy) and the effectiveness of the vaccine as previously evaluated in observational studies. Of the 5,707 studies screened, eligible trials were restricted to those evaluating the TIV and LAIV that included direct virus detection methods of reverse transcriptase – PCR or culture for confirmation of influenza. Ten randomized controlled trials assessed efficacy of the TIV during 12 influenza seasons and eight (67%) showed significant overall vaccine efficacy. Eight studies done in adults aged 18-64 during nine influenza seasons showed a pooled TIV efficacy of 59% (95% CI 51-67). Ten randomized controlled trials separately assessed the LAIV efficacy in healthy adults during 12 influenza seasons and nine (75%) were significant, with a pooled efficacy of 83% (CI 69-91). For the seasonal influenza vaccine, studies mainly analyzed the TIV. Six (35%) of 17 analyses showed significant effectiveness (lower 95% CI >0) against laboratory proven influenza. Review of this data showed that there were substantial gaps in efficacy data for both TIV and LAIV. No randomized controlled trials showed efficacy of TIV in people aged 2-17 or older than 65 years even met the stringent inclusion criteria of this analysis. And for LAIV, there are were no randomized controlled trials showing efficacy in people ages 8-59, despite AICP recommendations for use until age 49. With the evidence available, it can only be suggested that current influenza vaccines offer moderate overall protection against infection and illness. Although, seasonal influenza vaccines are reported to be 70-90% effective in prevention of laboratory-confirmed influenza, their effectiveness is difficult to comment on because of the varying incidence and unpredictable nature of seasonable influenza. So ultimately, whether or not you take the plunge and get vaccinated is a personal choice. The potential for efficacy and effectiveness certainly exists, but don’t be surprised if fevers, sniffles, and aches creep up on you after vaccination, as our data shows that vaccination by no means guarantees protection.

Adding more fuel to the fiery debate on the influenza vaccine is a study published this week by the International Journal of Obesity suggesting that obesity impairs the immune response to the influenza vaccine.[3] During the 2009 H1N1 pandemic, obesity was recognized as an independent risk factor for increased influenza morbidity and mortality.[4] Furthermore, obese mouse models have shown impaired innate immune responses and greater mortality following influenza infection.[5] This current prospective, observational study is the first to examine body mass index (BMI) on humoral and cell-mediated immune responses to the influenza vaccine in humans. The antibody response to the 2009-2010 TIV was assessed with convenience sampling in healthy weight, overweight, and obese patients at 1 and 12 months post-vaccination, and peripheral blood cultures were used to analyze CD 8+ T-cell activation. Data from the first 2 years of this ongoing study with 499 participants showed twelve months following vaccination, increasing BMI was associated with a larger drop in antibody titer. To test the cellular response, blood cultures 12 months post-vaccination were challenged with a live vaccine strain of influenza. Samples from obese individuals had decreased CD8+ T-cell activation. Given the increasing proportion of obesity in our society, we must keep this in mind when vaccinating our patients. Future studies could evaluate the need for higher doses or adjuvants to increase the immune response in obese individuals.

In other preventive medicine news, two particular studies evaluated interventions that could alter cancer risk. JAMA examined the association between alcohol consumption and breast cancer.[6] Previous studies have shown that higher alcohol consumption is associated with increased risk, but none have quantified this.[7] The Nurses’ Health Study, a prospective, cohort study of 105,986 women, used questionnaires to assess alcohol intake in early adulthood, followed by 8 subsequent surveys. The primary end point, a diagnosis of invasive breast cancer, occurred in 7,690 patients between 1980 and June 2008. The cancer risk was significantly increased at an alcohol intake of 5.0 to 9.9g per day, equivalent to 3-6 drinks per week (relative risk 1.15, 95% CI 1.06-1.24). There was also a weak association with binge drinking, but not frequency of drinking. Overall, a 10% increased risk of breast cancer was observed for each additional 10g per day of alcohol intake, a stronger effect than seen in previous studies. The authors hypothesized that the causative mechanism was the alcohol’s effects on circulating estrogen levels by increasing aromatase activity, decreasing hepatic catabolism of androgens, or effecting on adrenal steroid production. Although the mechanism is still unclear, this is one of the first studies to quantify the amount of alcohol needed to increase the breast cancer risk.

The second article added to the lengthy discussion about the effects of aspirin on the development of colorectal cancer (CRC).[8] Published in The Lancet, this study is the second in a series put forth by the Colorectal Adenoma/Carcinoma Prevention Program. The first, CAPP1, was a RCT that examined patients with familial adenomatous polyposis. The patients were randomized to aspirin and/or resistant starch v. placebo. After 1 year of follow-up, the authors concluded that both aspirin and resistant starches have decreasing protective effect against CRC. In CAPP2, the most recent trial, 1,071 participants with Lynch Syndrome were randomized to receive 600mg aspirin daily or placebo. The average length of observation was 25.2 months, followed by an average of 29 months of further follow-up. The initial study results, published in 2008, looked at CRC incidence in patients 6 years after the first group completed the study period. At that time, there was no evidence that aspirin or affected the development of colonic neoplasia. The current study is an extension to 10 years after recruitment. For the entire post-randomization period, the hazard ratio of CRC in the aspirin group was significant at 0.41 (CI 0.19-0.86, p=0.02) and argues for a strong influence of aspirin in decreasing the development of CRC. Secondary analysis also showed that greater duration of aspirin therapy decreased CRC incidence (0.06/100 person-years for those taking aspirin more than 2 years v. 0.13/100 person-years for less than 2 years). From this, the authors concluded that their findings support a delayed effect of aspirin on reducing CRC incidence. They went on to urge clinicians to “consider aspirin prescription for all individuals judged to be at high risk of colorectal cancer.” Despite their admonitions, we must remember that Lynch syndrome accounts for only 15% of the sporadic CRC cases.[9] This single study should not alter recommendations for CRC prevention without extensive further research.

Cystic fibrosis also made a guest appearance this week. NEJM published an international, randomized, double-blind, placebo-controlled trial showing success with a novel treatment for CF, the most common lethal genetic disease among white patients.[10] The investigational medication, Ivacaftor (VX-770), is an oral drug that is designed to increase the time that the cystic fibrosis transmembrane conductance regulator (CFTR) protein spends open at the epithelial cell surface. This should increase the flow of chloride and water into the mucous membrane. Until now, all treatments for CF have targeted the secondary effects of CFTR channels, but not the underlying cause of its dysfunction. In vitro studies have already shown that Ivacaftor augments the CFTR protein in the 4-5% of CF patients with the causative G551D missense mutation.[11] The study randomized subjects 12 years or older with at least one G55ID-CFTR mutation to receive either Ivacaftor or placebo for 48 weeks. The primary endpoint was mean change in %FEV1. At week 24, the %FEV1 in the Ivacaftor group improved 10.4 points, while that in the placebo group decreased 0.2 points. The effects of Ivacaftor was first noted by day 15 of treatment. At week 48, 67% of patients taking Ivacaftor were free from pulmonary exacerbations (v. 41% in the placebo group). Treated patients also had a 5.9 point improvement in the Cystic Fibrosis Questionnaire, compared to a 2.7 point decrease in the placebo group. Furthermore, treated patients also experienced a weight gain of 3.1kg v. 0.4kg in the placebo group. Adverse events for the two groups were similar. Because of the narrow population examined, though, additional studies are needed to evaluate the efficacy and safety profile of Ivacaftor before those afflicted by CF can truly celebrate.

As the runners fall into their post-marathon lull and the cold-air blues start to hit our patients, we are left standing on the edge of an era where medicine is becoming increasingly individualized. We should get a better idea of our patients’ constantly changing risk profiles and appreciate their unique differences. We can maybe even recall one of these newly examined interventions that could decrease long-term risk or, at the very least, encourage proactive behaviors in our patients. After all, acknowledging these subtle variations can help to maintain both the art and humanism of medicine.

Dr. Jessica Taff is a 1st year resident at NYU Langone Medical Center

Peer Reviewed by Ishmael Bradley, Section Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References: 

1. Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. The Lancet Infect Dis. Forthcoming Nov 2011. Available at: http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70295-X/fulltext

2. Fiore AE, Uyeki TM, Broder K, et al and the Centers for Disease Control and Prevention (CDC). Prevention and control of influenza vaccines: recommendations of the Advisory Committee on Immunization Practices (AICP), 2010. MMWR Recomm Rep 2010; 59:1-62. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr59e0729a1.htm

3. Sheridan PA, Paich HA, Handy J, et al. Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes. Forthcoming Nov 2011. Available at: http://www.nature.com/ijo/journal/vaop/ncurrent/full/ijo2011208a.html

4. Nave H, Beutel G, Kielstein JT. Obesity-related immunodeficiency in patients with pandemic influenza H1N. Lancet Infect Dis. 2011 Jan; 11:14-15. Available at: http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(10)70304-2/fulltext

5. Smith AG, Sheridan PA, Harp JB, Beck MA. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J Nutr. 2007 May. 137:1236-1243. Available at: http://jn.nutrition.org/content/137/5/1236.short

6. Chen WY, Rosner B, Hankinson SE, et al. Moderate Alcohol Consumption During Adult Life, Drinking Patterns, and Breast Cancer Risk. JAMA. 2011 Nov 3. 306(17) 1884-1890. Available at: http://jama.ama-assn.org/content/306/17/1884.abstract?sid=97a6daa9-dc18-4835-9d33-e5c06654d5ef

7.  Smith-Warner SA, Spiegelman D, Yaun S-S, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA. 1998: 279 (7): 535-540. Available at: http://jama.ama-assn.org/content/279/7/535.full?sid=894817e4-5458-411d-be2a-221197685d89

8.  Burn J, Gerdes A-M, Macrae F, et al Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. Forthcoming 2011. Available at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61049-0/fulltext#article_upsell

9.  Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998: 59(22)5248. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9823339

10. Ramsey BW, Davies J, McElvaney G, et al. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation. N Engl J Med. 2011 Nov 3; 365(18):1663-1672. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1105185?query=featured_home

11. Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA. 2009; 106: 18825-30. Available at: http://www.pnas.org/content/106/44/18825.full?sid=fe62f9b4-eda7-4c37-8639-fe8031fba14e

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