Primecuts – This Week In The Journals

February 3, 2015

By Kelley Coffman, M.D.

Peer Reviewed

The anti-vaccine movement appears to be gathering steam on social media and major media networks despite a growing outbreak of measles spreading to 8 states, according to California health officials report(1). The outbreak started in California’s Disneyland and has infected over 94 people. Once declared eliminated in the United States in 2000, measles is a highly contagious childhood viral respiratory illness characterized by fever, runny nose, cough, red eyes, sore throat with white spots on the oral mucosa, and a full body rash beginning on the face and spreading downward. The virus spreads through droplets in the air and can survive on surfaces for up to two hours. The CDC reports that 90% of non-immunized people in close contact with an infected individual will also become infected(2). Linked to further infections, seizures, miscarriages, birth defects, and even death, this easily preventable disease can wreak havoc on those infected.

Despite an effective vaccine against measles, mumps, and rubella licensed in 1971, this past year held the second-highest number of cases since measles was declared eradicated in the U.S. in 2000, with over 175 cases reported(2). In the few short weeks of the new year between January 1st and 28th, 84 cases linked to the Disneyland outbreak have been reported in 14 states(3). Much of the controversy over vaccination comes from a 1998 paper in The Lancet, which proposed a link between receipt of MMR vaccine and subsequent development of autism(4). This paper was retracted in 2010, but its impact on public opinion is long lasting. The recurrence of a once-eradicated disease in the US should prompt healthcare providers to question their role in advocating for vaccination among our patients.

A Monovalent Chimpanzee Adenovirus Ebola Vaccine – Preliminary Report

Few people would argue that a vaccine is needed for the highly contagious and lethal Ebola virus, which has, thus far, resulted in 8500 deaths in West Africa(5). Intense coverage of the Ebola outbreak has greatly declined among major U.S. media outlets, but fortunately, the scientific community continues to respond to this public health emergency. The New England Journal of Medicine published a preliminary report on the safety and immunogenicity of an experimental vaccine against the Ebola virus (Zaire strain) in a Phase 1, dose-escalation, open-label study in Oxford, United Kingdom(6). Enrolling 60 healthy adult volunteers, Rampling et al. evaluated the immune response to and side effects of a single dose of a monovalent vaccine encoded with a surface glycoprotein of Zaire ebolavirus (EBOV). The backbone of the vaccine consisted of a well-established vector using the chimpanzee adenovirus 3 (ChAd3), which was developed by the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases in collaboration with Okairos, with clinical assessment beginning in 2007. The ChAd3 vaccine is typically used in conjunction with an MVA (modified vaccinia virus Ankara) booster dose.

During this Phase I trial, participants received a single injection of the vaccine with dose determined by group assignment. The majority of adverse events including fever, prolonged aPTT, and transient hyperbilirubinemia were considered mild and short-lived with no major safety concerns identified during the 180-day follow-up after vaccination. Immune response against the EBOV surface glycoprotein was demonstrated by ELISA-detection of increased antibody titers from the patients’ baseline levels within each group (p<0.001), albeit, with a weak dose-response relationship. Maximal mean response occurred after four weeks. Additionally, the white blood cells of each vaccinated participant were ran through an ELISpot assay, a widely used, highly sensitive method to monitor the effectiveness of a vaccine to induce an antigen-specific T-cell response. In this assay, the number of spot-forming cells (SFCs) increases proportionately with strength of the immune response. The predominately CD4+ T-cell response in the EBOV-vaccinated participants peaked at day 14 with 100% of participants in the high-dose group showing a positive response to the vaccine with approximately 700 SFCs, a significant increase over the background pre-vaccination level of approximately 50 SFCs. The authors recommended strengthening immunogenicity by either using a higher dose of vaccine or by boosting it with an MVA vector encoded with the same antigen.

Although this vaccine may show promise, its role in the current outbreak in West Africa will likely remain limited. African populations may mount a reduced immune response to viral-vectored vaccines in comparison to northern Europeans according to prior research(7,8). Thus, inclusion of patients from disease-endemic countries in further trials of this vaccine will be paramount; the medical literature will undoubtedly continue to chronicle the success or failure of this vaccine.

Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials

As flu season continues and overall resistance to vaccination grows, the results of a meta-analysis on the use of oseltamivir for treatment of influenza in adults could not be better timed. This recent publication by The Lancet attempts to address the controversial efficacy and safety of oseltamivir. This industry-funded study gathered individual patient-level data from nine published and unpublished double-blind RCTs, including 4328 patients(9). The meta-analysis evaluated both an intention-to-treat population and an intention-to-treat-infected population (i.e. laboratory confirmed influenza with PCR testing or elevated antibody titers) in order to highlight both overall drug exposure and its efficacy specifically in influenza, respectively. Patients with a fever and at least two influenza symptoms (one respiratory: cough, sore throat or coryza; and one constitutional: headache, myalgia, sweats or chills, or fatigue) were treated within 36 hours of feeling unwell with 75mg every 12 hours for five days and followed for resolution of symptoms as well as adverse side effects.

The meta-analysis showed that use of oseltamivir in adult patients with influenza reduced the duration of flu-like symptoms by 21% (time ratio 0.79, 95% CI 0.74-0.85, p<0.0001) from 122.7 to 97.5 hours. Antiviral treatment of influenza-infected participants also reduced the complications of lower respiratory tract infections by 44% (RR 0.56, 95% CI 0.42-0.75, p=0.0001) and hospital admissions by 63% (RR 0.37, 95% CI 0.17-0.81, p=0.013). Importantly, these findings did not hold true in a subgroup analysis of high-risk patients including the elderly and patients with chronic illnesses or chronic obstructive airway disease at baseline, with no statistically significant difference shown in time to alleviation of all symptoms between treatment and placebo groups. Adverse effects were mainly limited to nausea and vomiting. Although a recent BMJ systematic review on oseltamivir reported a dose-response effect on psychiatric events(10), this association was not reproducible in this meta-analysis at the 75mg “standard” dose. The authors suggest that the 150mg “high” dosing schedule may be responsible for the difference in study results. Overall, the ITT analysis also demonstrated these findings but with an attenuated effect, suggesting that the benefits of using oseltamivir in patients suspected to be infected with influenza would outweigh its minimal risks. However, this risk-benefit analysis may be further skewed in a population with a lower prevalence of influenza, so in the absence of rapid testing for influenza, are we obligated to initiate treatment for highly suspicious cases of the flu?

Hyperlipidemia in Early Adulthood increases Long-term Risk of Coronary Heart Disease

Moving on from acute, infectious diseases to chronic, cardiovascular conditions, an article published last week in Circulation(11) may add to the monumental changes to primary prevention of cardiovascular disease brought about by the 2013 AHA/ACC cholesterol guidelines(12). These guidelines recommend initiating a lipid-lowering drug for all adults with prevalent CVD, LDL-C > 190mg/dl, diabetes, or 10-year risk of atherosclerotic CVD > 7.5%. This more liberal approach is resulting in a high number of older adults aged > 60 years considering statin therapy; however, a grey zone still exists among those younger adult patients with hyperlipidemia who don’t quite meet the aforementioned recommendations. Navar-Boggan et al. broached this topic by re-evaluating the Framingham Offspring Cohort data to identify patients with prolonged exposure to moderate hyperlipidemia (non-HDL-C > 160mg/dL) during early adulthood that subsequently developed coronary heart disease (CHD). The study design selected patients in their 5th decade of life who were free of CVD (defined as MI, angina, coronary insufficiency, transient ischemic attack, stroke, coronary heart disease death, cardiovascular death, intermittent claudication, or heart failure) and prospectively followed their development of CHD over the following 15 years. The rate of CHD significantly increased according to duration of exposure to hyperlipidemia during early adulthood (age 35-55): 4.4% for those with no exposure, 8.1% for 1-10 years, and 16.5% for those with 11-20 years exposure (p<0.001). This dose-dependent relationship remained significant after adjusting for other cardiac risk factors (age, sex, systolic blood pressure, antihypertensive treatment, HDL cholesterol, diabetes, and smoking).

The authors conclude that cumulative exposure to hyperlipidemia in young adulthood might be an equally important consideration when discussing lifestyle intervention or even treatment with patients who don’t fall under the current guidelines for lipid-lowering therapy. Prediction models for CVD risk may improve their accuracy by incorporating lifetime risk, rather than limiting to 10 years. At a minimum, we, as providers, shoulder consider screening our younger adult patients and discussing more aggressive prevention in our “low risk” middle-aged patients with prolonged exposure to hyperlipidemia.

A Randomized Trial of Icatibant in ACE-Inhibitor–Induced Angioedema

As ACE-inhibitors (ACEI) continue to become a staple in primary care, the incidence of ACEI-induced angioedema is expected to increase(13). The mechanism of this well-established side effect theoretically results from the accumulation of bradykinin due to inhibition of its ACE-mediated breakdown. An estimated one-third of Emergency Department visits for angioedema are related to ACEI use(14), and despite knowledge of its (specific) pathogenesis, the standard therapy still consists of (non-specific) glucocorticoids and antihistamines. In last week’s NEJM, Bas et al. challenged this practice by proposing the off-label use of a selective bradykinin B2 inhibitor, icatibant, as an alternative treatment for ACEI-induced angioedema(15). In this multicenter, double-blind, double-dummy, randomized phase 2 study in Germany, the time to complete resolution of angioedema was compared between standard therapy (IV prednisolone 500mg plus oral clemastine 2mg) and icatibant (30mg, subcutaneous). The 27 patients in the per-protocol demonstrated ACEI-induced angioedema of the upper aerodigestive tract (face, lips, cheeks, tongue, soft palate or uvula, pharynx, and larynx). A scale, using a combination of patient-reported and investigator-observed reduction of symptoms as well as physical exam findings, determined improvement of angioedema at different time-points between 0-48 hours post-treatment. The bradykinin inhibitor reduced duration of symptoms by a remarkable 70% (8.0 hours vs. 27.1 hours, p=0.002). Unfortunately, the small sample size and per-protocol analysis of this study limit its applicability; if reproduced in a larger trial with a more rigorous analysis, these findings could be practice changing. Regardless, this trial should serve as a reminder that our standard practices do not always align with our knowledge of disease – maybe we should go back to the basics as we pick up our pen to write our next prescription.

In other news:

The Journal of American College of Cardiology also looked at expanding primary prevention of cardiovascular disease to younger patients(16). The Chicago Heart Association Detection Project in Industry Study evaluated 31-year risk for cardiovascular mortality in over 15,000 men and 11,000 women between 18 to 49 years of age with hypertension. Risk of cardiovascular disease and death was increased in men and women with isolated systolic hypertension).

The New England Journal of Medicine also continued with the trend of cardiovascular prevention this week in a special article on the cost-effectiveness of 2014 hypertension guidelines(17). Using a simulation model, the authors found that full implementation of these new guidelines could prevent approximately 56,000 cardiovascular events and 13,000 deaths annually. Cost-savings were seen in all patients with cardiovascular disease or stage 2 hypertension. Notably, cost-effectiveness was reduced in women aged 35-44 years old with stage I hypertension but no CVD.

A meta-analysis published in BMC Medicine(18) found that the use of mineralocorticoid receptor antagonists may also be beneficial in heart failure patients with preserved ejection fraction. Treatment led to reduced hospitalizations, better quality of life, and improved diastolic function; however, no all-cause mortality benefit was found in the study by Chen et al.

Dr. Kelley Coffman is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Mark H. Adelman, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


1. Fox M. Disney Measles Outbreak Came from Overseas, CDC says. NBC Health News. 1/29/15.

2. Haynes A. 5 things to know about measles. CNN Health. 1/30/15.

3. Transcript for CDC Telebriefing: Measles in the United States, 2015.

4. Wakefield AJ, et al. RETRACTED: Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet. 351(9103): 637-641.

5. Ebola response roadmap – situation report. Geneva: World Health Organization.

6. Rampling T, et al. A Monovalent Chimpanzee Adenovirus Ebola Vaccine – Preliminary Report. N Engl J Med. Published online 1/28/2015

7. Kimani D, et al. Translating the immunogenicity of prime-boost immunization with ChAd63 and MVA ME-TRAP from malaria naïve to malaria-endemic populations. Mol Ther 2014; 22: 1992-2003.

8. Bejon P, et al. The induction and persistence of T cell IFN-gamma responses after vaccination or natural exposure is suppressed by Plasmodium falciparum. J Immunol 2007; 179: 4193-4201.

9. Dobson J, et al. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. The Lancet. Published online 1/29/15

10. Jefferson T, et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 248: g2545.

11. Navar-Boggan, et al. Hyperlipidemia in Early Adulthood Increases Long-term Risk of Coronary Heart Disease. Circulation. Published online 1/26/2015

12. Goff DC, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25_PA):2935-2959.

13. Holm JPY, Ovesen T. Increasing rate of angiotensin-converting enzyme inhibitor-related upper airway angio-oedema. Dan Med J 2012; 59: A4449.

14. Banerji A, Clark S, Blanda M, LoVechio F, Snyder B, Camargo CA Jr. Multi-center study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department. Ann Allergy Asthma Immunol 2008; 100: 327-32.

15. Bas M et al. A Randomized Trial of Icatibant in ACE-Inhibitor–Induced Angioedema. N Engl J Med 1/29/2015; 372: 418-25.

16. Yano Y et al. Isolated Systolic Hypertension in Young and Middle-Aged Adults and 31-Year Risk for Cardiovascular Mortality. J Am Coll Cardiol. 2015; 65(4): 327-335.

17. Moran AE et al. Cost-Effectiveness of Hypertension Therapy According to 2014 Guidelines. N Engl J Med 2015; 372: 447-455.

18. Chen Y et al. Effects of mineralocorticoid receptor antagonists in patients with preserved ejection fraction: a meta-analysis of randomized clinical trials. BMC Medicine 2015; 13:10.