This was a week of confusion both old and new. How did a chance of flurries become a major winter storm? Did Beyoncé sign “Happy Birthday” to first lady Obama? What strain of cholera caused the 1849 Philadelphia Pandemic?
This week’s medical literature may not have cleared up all these pressing questions, but at least it managed to determine the strain of Vibrio cholerae that caused the devastating Philadelphia cholera outbreak of 1849. Vibrio cholerae’s predominate pathogenic strain—serogroup O1—has two genetically different biostrains: classic and El Tor. For unknown reasons in the 20th century, El Tor replaced classic as the predominate pathogenic biotype. This week the New England Journal of Medicine (NEJM) report helped confirm the timeline of this transition and investigate its possible reasons. From the 150 year-old preserved intestines of a pandemic victim, Vibrio cholerae DNA was extracted, sequenced, and compared to current day classic genotype O395. The DNA from the 1849 pandemic had 95-97% similarity to classical O395 Vibrio cholerae genome, helping demonstrate that the classic biostrain was the predominate pathogen during this period. Genome comparisons also provided possible reasons for the change in the predominant cholera pathogen. The cholera sample from the 1849 victim had longer tandem arrays of cholera toxin phage (CTX) than current-day O395 classic Vibrio cholerae. CTX is the main virulent factor. These tandems suggest possibly increased virulence, but the actual functional implications remain unclear—these repeats could possibly be uncoded and without actual pathologic significance .
And if you were worried that this confusion was just secondary to early dementia, well…you should probably continue to be really worried. Two studies published this week in the NEJM investigating monoclonal antibody therapies as treatments for Alzheimer’s disease failed to show benefit. Both studies involved targeting amyloid-beta as a means to reduce plaque formation with hopes of at least sustained mental status in patient’s with mild-to-moderate Alzheimer’s disease.
The first study investigated solanezumab, a humanized monoclonal antibody that binds to soluble amyloid-beta, with two double-blind trails (EXPEDITION 1 and EXPEDITION 2) involving about 2,000 patients in all. Four hundred milligrams of solanezumab was infused every 4 weeks for 18 months. Clinical outcome was based on the 11-item cognitive sub-scale of Alzheimer’s Disease Assessment Scale (ADAS-11), 14-item cognitive sub-scale of Alzheimer’s Disease Assessment Scale (ADAS-14), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL). In the EXPEDITION 1 trail, the ADAS-11 score (higher scores signify worsening cognitive ability) was increased in both groups. Scores increased by 4.5 (95% CI, 3.3 to 5.8; P = 0.24) and 3.8 (95% CI, 2.5 to 5.0; P = 0.24) in the placebo verse treatment group, respectively; however, confidence intervals overlapped. Investigation with ADAS-14 which is considered a more sensitive indicator of cognitive ability in mild dementia showed similar results; the scores increased from baseline in both group with overlapping confidence intervals. The ADAS-14 scores for this study for placebo versus intervention were 5.8 (95% CI, 4.3 to 7.3, P = 0.09) and 4.5 (95% CI, 2.9 to 6.0, P = 0.09). ADCS-ADL (where lower scores indicate decreased ability) were lower in both the placebo and solanezumab-treated group at the end of 18 months, decreased by -8.7 (95% CI, -10.4 to -7, P = 0.64) versus -9.1 (95% CI, -10.9 to -7.4, P = 0.64) from baseline, respectively. However, confidence intervals again overlapped. These ambivalent findings were also replicated in the EXPEDITION 2 trial. The study’s authors theorized that possible efficacy would be derived in patients with very early disease and larger powered studies (p-values were greater than 0.05 in many of the investigated outcomes) .
A separate NEJM-published trial investigated bapineuzumab, another humanized anti-amyloid beta monoclonal antibody that binds to fibrillar, oligomeric, and monomeric forms. Results for this treatment were also lackluster. Two double-blind trials involved approximately 2500 patients with confirmed carriers and non-carriers of apolipoprotein E (APOE) epsilon4 allele—a lipoprotein associated with Alzheimer’s disease. Clinical outcome was measured again by the ADAS-11 and the Disability Assessment for Dementia (DAD), as well as CSF analysis and brain imaging in a random study subpopulation. Results showed no benefit in the intervention group versus placebo in both the carriers and non-carriers at doses of 0.5mg per kilogram and 1mg per kilogram every 13 weeks for 78 weeks. CSF showed decreased phospho-Tau concentration—a biomarkers of amyloid—and positron-emission tomographic amyloid imaging with Pittsburgh compound B (PIB-PET) showed decreased amyloid only in treated carriers of APOE epsilon4 allele. However, no clinical benefit or decreased MRI brain degeneration was obtained in comparison of the placebo versus treated carriers of APOE versus treated non-carriers. Also there were again observed increase rates of cerebral edema in carriers at higher doses of bapineuzumab. Per the study’s authors, amyloid accumulation probably starts many years before the onset of symptoms and anti-amyloid therapy after the onset of dementia may be too late in the clinical course to be of benefit .
So basically two NEJM articles said if you think you are developing dementia, it’s already too late for any possible benefit from these medical therapies. You should probably see your doctor…soon.
And if you wonder at the end of the day if all your efforts are actually helpful, well the literature shows mixed results on that too.
The Lancet published findings on global and regional stroke burden from 1990 to 2010 that compared incidence, mortality, disability and trends in high, low, and middle-income countries. To estimate global and regional burden of stroke during this period, researchers searched online medical databases for stroke related studies from 1990 to 2010 and applied statistical models that addressed incomplete epidemiological data first developed by he Global Burden of Diseases, Injuries, and Risk factors Study 2010 (GBD 2010). Results showed decreased age-standardized incidence of stroke by 12% (95% CI, 6 to 17) in high-income countries. Stroke incidence showed possible increase in both middle and low-income countries. In both middle and low-income countries, stroke incidence increased by 12% (95% CI, -3 to 22); however, findings were non-significant as the confidence interval crosses zero indicating chance of possible decreased rates. Stroke mortality rates decreased significantly in all countries. In high-income countries mortality decreased by 37% (95% CI, 31 to 41). In both middle-income and low-income countries, mortality decreased by 20% (95% CI, 15 to 30) This research also showed increased absolute numbers of stroke incidence, mortality, and morbidity concentrated in low and middle-income countries with significantly unequal geographic distribution—most predominately in Russia and its former satellite states, China, the Middle East, and southern Africa .
NEJM also published an investigation of diagnosis-associated adverse-event rates among Medicare patients with common medical conditions. Basically, researchers abstracted data from the Medicare Patient Safety Monitoring System (MPSMS) looking for adverse events in patients hospitalized for myocardial infarction, congestive heart failure, pneumonia, and conditions requiring surgery between the years 2005 and 2011. Adverse events included events associated with digoxin or anticoagulation, pressure ulcers, inpatient falls, hospital-acquired infections including ventilator-associated pneumonia, line/catheter-related, MRSA, Clostridium difficile colitis, intra-operative and post-surgical adverse events. Investigating a population of 61,523 patents, researchers determined that adverse events in myocardial infarction decreased from 5% to 3.7% over the 2005 to 2011 time period. Among inpatient congestive heart failure admissions, adverse events decreased from 3.7% to 2.7%. However, patients with pneumonia and those conditions requiring surgery had no significant change in adverse events. Rate of adverse events in patient admitted for pneumonia was 3.4 in 2005 and 3.5 in 2011 For conditions requiring surgical intervention, rate of adverse events was 3.2 in 2005 and 3.3 in 2011. This study suggested that although some inroads have been made in patient safety, there is still a disappointing lack of reductions across the board per the study’s authors .
Also in the literature this week:
1. The Mayo Clinic investigated risk stratification in patients hospitalized for community-acquired pneumonia based on age, preexisting conditions, vital signs, as well as laboratory and radiographic parameters that help place patients in 4 categories indicating risk of cardiac complications .
2. The Cleveland Clinic addressed obesity in the elderly, concluding that waist circumference may be a more appropriate gauge of weight status .
3. European researches investigated if there was a relationship between coronary events and exposure to polluted air. They found that populations in polluted ambient environments had increased risk of coronary events event when adjusted from sociodemographic and lifestyle risk factors .
4.This week the Annals of Internal Medicine investigated the risk of cardiovascular disease after giant-cell arteritis, finding that there is increased risk of MI. CVA, and PVD in both early and late follow-up periods .
And if this week has you down, think about the potential prospects for the last karaoke of the year that does not include Matt McNeill’s caterwauling: http://www.mirror.co.uk/3am/celebrity-news/beyonce-crashes-karaoke-party-kelly-3002843#.UuFrB6X0DQs
Dr. Luke O’Donnell is a 1st year resident at NYU Langone Medical Center
Peer reviewed by Arnab Ghosh, MD, Contributing Editor, Clinical Correlations
Image courtesy of Wikimedia Commons
1. Devault AM, Golding GB, Waglechner N et al. Second-Pandemic Strain of Vibrio Cholerae from the Philadelphia Cholera Outbreak of 1849. New England Journal of Medicine 370(4); 334-340. 2014. http://www.nejm.org/doi/full/10.1056/NEJMoa1308663
2. Doody RS, Thomas RG, Farlow M et al. Phase 3 Trails of Solanezumab for Mild-to-Moderate Alzheimer’s Disease. New England Journal of Medicine 370(4); 311-321. 2014. http://www.nejm.org/doi/full/10.1056/NEJMoa1312889
3. Salloway S, Sperling R, Fox N et al. Phase 3 Trails of Bapineuzumab for Mild-to-Moderate Alzheimer’s Disease. New England Journal of Medicine 370(4); 322-333. 2014. http://www.nejm.org/doi/full/10.1056/NEJMoa1304839
4. Feigin VL, Forouzanfar MH, Krishnamurthi R et al. Global and Regional Burden of Stroke During 1990-2010: Findings from the Global Burden of Disease Study 2010. The lancet 383(9913); 245-255. 2014. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61953-4/fulltext
5. Wang Y, Eldridge N, Metersky ML et al. National Trends in Patient Safety for Four Common Conditions, 2005- 2011. New England Journal of Medicine 370(4); 341-351. 2014. http://www.nejm.org/doi/full/10.1056/NEJMsa1300991
6. Corrales-Medina VF, Taljaard M, Fine MJ et al. Risk Stratification for Cardic Complications in Patients Hospitalized for Community-Acquired Pneumonia. Mayo Clinic Proceedings 89 (1); 60-68. 2014. http://www.mayoclinicproceedings.org/article/S0025-6196(13)00927-0/abstract
7. Cetin DC, Nasr G. Obesity in the elderly: More complicated than you think. Cleveland Clinic Journal 81(1); 51-61. 2014. http://www.ccjm.org/content/81/1/51.abstract
8. Cesaroni G, Forastiere F, Stafoggia M et al. Long term exposure to ambient air pollution and incidence of acute coronary events: a prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE project. British Medical Journal 348. 2014. http://www.bmj.com/content/348/bmj.f7412
9. Tomasson G, Peloquin C, Mohammad A et al. Risk for Cardiovascular Disease Early and Late After a Diagnosis of Giant-Cell Arteritis: A Cohort Study. Annals of Internal Medicine 160(2). http://annals.org/article.aspx?articleid=1814422