Primecuts – This Week In The Journals

June 1, 2015

By Samir Bhalla, MD

Peer Reviewed

Earlier this week, 14 individuals with ties to FIFA were indicted by US attorney general Loretta Lynch on charges of racketeering, corruption and conspiracy. A collaborative Swiss investigation remains underway to assess for corruption with regards to the 2018 and 2022 World Cup bids. These indictments raise questions into the integrity of FIFA, however will hopefully lead to significant improvements within the organization governing the world’s most popular sport.

Efficacy and Safety of a Recombinant Herpes Zoster Vaccine [1]

Speaking of improvements, the NEJM this week published the results of a landmark phase 3 clinical trial regarding the safety and efficacy of a recombinant varicella zoster virus (VZV) vaccine. Zostavax, the currently used live attenuated vaccine is estimated to be 51.3% efficacious for prevention of herpes zoster and 66.5% for post-herpetic neuralgia. These efficacy rates for the vaccine have been noted to decline with advancing patient age. Combined with inability to utilize the vaccine in immunocompromised patients, efforts have been made to create an improved and recombinant VZV vaccine.

HZ/su, produced by GlaxoSmithKline is a recombinant vaccine comprised of a VZV glycoprotein and a supplemental antigen which serves to enhance T cell response. This phase 3 large, multi-national, randomized clinical trial of over 15 thousand patients assessed the efficacy and safety of the vaccine compared to placebo. Enrolled patients over the age of 50 with no prior history of shingles or prior VZV vaccination were randomized and stratified by age to receive two doses of the vaccine or placebo. Following administration of the vaccine or placebo, patients were followed for nearly 30 months for development of herpes zoster, with cases confirmed by PCR testing of three skin lesions. Additionally, subgroups of each treatment arm were monitored for development of adverse reactions, titled the reactogenicity subgroup. The treatment arms were balanced with regards to age and sex of participants, however of note, the majority of patients were female and of Caucasian ethnicity.

The incidence of herpes zoster (HZ) was significantly decreased among all age groups in the vaccinated group as compared to placebo group, with an overall efficacy rate of 97.2%. This corresponds to a NNT of 36 and absolute risk reduction of 2.8%. Analysis of the reactogenicity subgroups revealed an increase in both local and systemic reactions within 7 days of administration of the vaccine compared to placebo. There was no significant difference in adverse effects beyond 30 days from administration.

Thus, the HZ/su recombinant vaccine decreased the incidence of herpes zoster with no significant change in efficacy with advancing age compared to placebo. This data shows enhanced efficacy compared to the published efficacy rates of Zostavax, however the two vaccines were not directly compared in this study.

Non-Invasive Ventilation for Hypoxemic Respiratory Failure [2]:

The use of non-invasive positive pressure ventilation (NIPPV) has become commonplace in inpatient medicine and has proven benefits for the management of acute respiratory failure secondary to COPD exacerbations and cardiogenic pulmonary edema. In patients with acute hypoxic respiratory failure, however, the best method of non-invasive ventilation is less well characterized.

In this week’s NEJM, Frat et al. published the results of their randomized clinical trial evaluating the relative efficacy of high flow nasal cannula versus standard nasal cannula and NIPPV in the management of acute hypoxic respiratory failure.

In the study, 310 patients with acute hypoxic respiratory failure, defined by PaO2/FiO2 ratio less than 300 and PCO2 no greater than 45 who did not require emergent intubation, were enrolled. Patients were randomized to three subgroups on admission; standard oxygen therapy, high flow nasal cannula for at least 2 days, or NIPPV for at least eight hours a day for 2 days. The patients were subsequently followed to assess for need for intubation within 28 days as the primary outcome and secondary outcomes of mortality in the ICU and within 90 days, and the number of ventilator free days.

Analysis of the results showed no significant difference in the need for intubation within 28 days of admission between the three groups. When focusing on severely hypoxemic patients with PaO2/FiO2 less than 200, however, high flow nasal cannula did produce a lower rate of intubation as compared to standard oxygen therapy and NIPPV. Additionally, patients in the high flow nasal cannula treatment group had a statistically significant increase in ventilator free days and reduction in 90 day mortality. This study, therefore, provides further generalizable evidence for the growing use of high flow nasal cannula in patients with acute hypoxemic respiratory failure.

Evidence for non-operative management for appendicitis? [3]

Although acute appendicitis is not a frequently encountered diagnosis in internal medicine, the dogma of early surgical intervention is engrained into the minds of nearly all physicians. This is a point that is heavily emphasized in medical school and board examinations. In this week’s New England Journal of Medicine, however, Flum provides a comprehensive review of the management of acute appendicitis and details evidence behind an “antibiotics-first” approach.

Interestingly, the first data on the so-called “antibiotics-first” strategy came from Naval officers who developed acute appendicitis while on active duty. Since this time, many randomized trials have investigated urgent appendectomy versus initiation of antibiotics for 48 hours, and delayed appendectomy if deemed necessary. It is difficult to produce a meta-analysis of the outcomes of these studies due to the large variability in treatment protocols and outcomes measured. As described by Flum, clinical outcomes were generally favorable for patients assigned to an antibiotic-first strategy. When compared to early appendectomy, patient’s who received antibiotic based treatment did not have a statistically significant higher risk of perforation, had decreased reported pain scores, and returned to work sooner. The frequency with which patients assigned to antibiotic treatment needed to be converted to urgent surgery ranged from 0-53%. This wide range of conversion to surgery has been attributed to use of different levels of adherence to antibiotic approach and varying criteria to assess need for surgery.

Questions still remain regarding the antibiotic regimen of choice, risk of recurrence, and the eventual need for appendectomy in patients managed acutely with antibiotics. Further standardized clinical trials will be needed to address these questions, and therefore the current recommendations still favor urgent appendectomy for acute uncomplicated appendicitis. There clearly is growing evidence, however, that non-operative antibiotic treatment is a reasonable strategy, especially in patients with contraindications to surgery.

Oral Steroids for Acute Radiculopathy Due to a Lumbar Herniated Disc [4]

Acute radiculopathy is a common presenting complaint in outpatient medicine, with estimates reporting a lifetime prevalence of nearly 10%. For the majority of patients, the likelihood of spontaneous resolution is high, and therefore management is geared towards symptomatic treatment only. For patients with persistent symptoms, however, the role of epidural spinal injections (ESI) and surgical interventions has been growing. Systemic glucocorticoids are often used by outpatient physicians, but the efficacy has not been investigated thoroughly, prompting the study published by Goldberg et al. in this week’s JAMA.

Patients presenting with radicular pain and MRI imaging confirming lumbar disc herniation as the etiology were randomized to receive a 15 day taper of prednisone or placebo. The Oswestry Disability Index (OSI) and Numerical Rating Scale (NRS) were used as markers for the patient’s degree of symptoms and pain. Analysis of the data showed that patients in the steroid arm of the trial had a statistically significant greater reduction in OSI than compared to placebo group at both 3 weeks and 52 weeks after treatment initiation. There was no significant reduction in reported pain measured by NRS at 3 or 52 weeks of follow up. The use of steroids was associated with a statistically significant higher rate of adverse effects including insomnia, nervousness, and appetite increase within 3 weeks, but no significant difference in long term adverse effects. Most importantly, there was no significant difference in the need for eventual spinal surgery between the groups at 1 year of follow up.

Thus, while often used for the management of acute radiculopathy, this study shows that oral steroids provide a decrease in disability and activity restriction, but without any significant change in pain or eventual need for surgery.

Also in the journals this week:

What is the evidence and guidelines regarding the use of beta blockers peri-operatively for both cardiac and non-cardiac surgeries?

Should supplemental oxygen be given to all patients presenting with STEMI? This article published in Circulation reveals increased mortality associated with providing supplemental oxygen to patients with STEMI but without hypoxia.

An update on the development of an Ebola vaccine:

Dr. Samir Bhalla is a 1st year resident, Internal Medicine, at NYU Langone Medical Center

Peer reviewed by Gregory Schrank, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


1) Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015;372:2087-2096

2) Frat JP, Thille AW, Mercat A, et al. High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. N Engl J Med. 2015; DOI: 10.1056/NEJMoa1503326

3) Flum DR. Clinical practice. Acute appendicitis–appendectomy or the “antibiotics first” strategy. N Engl J Med. 2015;372(20):1937-43. DOI:+10.1056/NEJMcp1215006

4) Goldberg H, Firtch W, Tyburski M, et al. Oral Steroids for Acute Radiculopathy Due to a Herniated Lumbar Disk: A Randomized Clinical Trial. JAMA. 2015;313(19):1915-1923. doi:10.1001/jama.2015.4468.