Infectious Diseases Blog

History as teacher

At the University of Pittsburgh School of Pharmacy, one of the major historical links between viruses and cancer hits very close to home (yes, we sometimes do feel as if we live in Salk hall).The Salk inactivated polio vaccine, which was hugely successful in preventing polio, was found to be contaminated with Simian Virus 40 (SV40) several years after it had already been administered to millions of Americans.The further observation that SV40, a “monkey virus” which infected the rhesus kidney cells in which the vaccine was produced, caused transformation of several nonhuman cell lines into cancerous cells caused great alarm and led to intense study of the link between cancer and the virus, and the possible ramifications of exposure.While the jury is still out (and most likely is out for good[1]) on whether or not this contamination led to an increased rate of cancer in exposed individuals, scientists’ intense scrutiny of the virus contributed to the discovery of one of the archetypical tumor suppressors, the retinoblastoma (Rb) protein. The SV40 viral protein dubbed “large T antigen” inactivates Rb, thereby mitigating its critical role in cell cycle regulation.Loss of Rb-mediated cell cycle control can lead to enhanced proliferation and, when combined with additional cumulative genetic or epigenetic changes, can lead to overt cancer.While issues of infectivity and transmissibility may hamper SV40’s contribution to the development of human cancers, the role of HPV in causing human cervical cancer has been established with much more certainty.Interestingly, HPV also encodes a viral protein named E7 which inactivates the Rb tumor suppressor and gives infected cells a growth advantage, ultimately leading to cervical cancer in a fraction of infected individuals. Thus, while a vaccine to “prevent all cancers,” may be unrealistic at this point in time, when we consider the multitude of ways cancers emerge in the human body, it can be appreciated that we have been able to develop several vaccines against specific, known etiologic agents.

For discussion

[1] Fisher SG, Weber L, Carbone M. Cancer risk associated with simian virus 40 contaminated polio vaccine. Anticancer Res. 1999;19(3B):2173-80.

Here are 7 steps to prevent vaccination errors:

-Blogger's note: This entry was penned by PharmD candidate Justin Montgomery while completing the Infectious Diseases APPE rotation at UPMC Presbyterian.

There’s good news for those of us who like to hit the gym or go for a run on a regular basis. According to a recent study by Kohut et. al published in the Journal of Infectious Diseases, repeated moderate exercise shows an increased benefit over acute exercise when it comes to reducing some common symptoms associated with influenza infections. In this study, mice were used to model the protective effect of exercise on both the induction and severity of symptoms of a course of influenza infection. Mice were randomized to either a no exercise control group, a chronic exercise group consisting of mice that exercised 5 days a week for 14 weeks at moderate intensity, and an acute exercise group consisting of mice that ran for 45 minutes on a treadmill only on the day of infection. The chronic exercise group was infected intranasally with influenza virus 24 hours after completing their last exercise session and the acute exercise group was infected intranasally 15 minutes after finishing on the treadmill. The mice were then euthanized and examined at either 2, 5 or 10 days.

Why Distance is Important

Greeting Transmission Risk

In summary, in the context of a viral pandemic, it's probably best to avoid the "Bro-Hug" or other close greetings. I suggest sticking with the fist bump (the elbow rub seems awkward and may challenge uncoordinated individuals!!).

Did you ever wake up one morning and think to yourself:

"I can handle an influenza pandemic, no problem"?

Me too! So here's your chance to prove it. Check out this web based simulation game that puts you in control of fighting various viral pandemics. You've got a budget, various weapons in your infection control arsenal, and the world. Your job is to deploy your infection control measures to limit viral transmission and death within and across continents.

Have you ever seen the movie WarGames circa 1983 starring Matthew Broderick (three years prior to starring in the '80's classic Ferris Bueller's Day Off)? The one where he challenges a computer program to Global Thermonuclear War, but the stakes are (almost) real? This game is in that vein. Try it out! www.thegreatflu.com

For data interpretation, I’ll play the role of pundit. Within Question 4 below, your agreement was asked regarding five specific statements. The responses could be Strongly Disagree; Disagree, Neither Agree nor Disagree; Agree; or Strongly Agree. Each answer was weighted from 1 to 5 respectively. Unfortunately, the data could not be filtered by pharmacy related job. Some notable observations:

As political pundits would tell you, polls (data in general) can be spun in many ways. Before we take our perceptions as fact, consider what one of your colleagues stated in an e-mail to me regarding the “cheap generics” program:

The cheap generics program was created by “. . . a community pharmacist who noticed many of his customers were moving to mail order. He felt this was a bad idea as it led to decreased patient contact so he began to offer his cheap generics . . . .” These programs “. . . save people money and keep mail order from monopolizing the pharmacy
business”. Well said. We know that pharmacists through patient interaction and participation in patient care can improve patient outcome and lead to the safe and effective use of medications. In that respect, no spin is necessary.

This past Sunday, September 28, 2008, marked an important date in the history of mankind. It was the 80th anniversary of Sir Alexander Fleming’s discovery of penicillin. Specifically, Sir Fleming noticed that a mold contaminating a plate of Staphylococci in his laboratory had produced a zone of Staphylococcal growth inhibition. His conclusion: The contaminating mold (Penicillum notatum) was producing an unknown substance that was responsible for the inhibition of Staphylococcal growth. The antibiotic era had begun.

Much has transpired since the 1920’s. In the context of this blog, I’m referring to bacterial resistance. Bacteria intent on survival are keen to acquire or create new mechanisms of resistance due to antibiotic pressure. Over time, penicillin has fallen victim to these resistance mechanisms, which are now widespread in many Gram-positive organisms, particularly Staphylococci. For example, of the 2,054 non-duplicate isolates of Staphylococcus aureus tested for penicillin susceptibility at UPMC Presbyterian in 2007, only 9% were susceptible. This is a far cry from Sir Fleming’s time when resistance was likely to be less than 1%. As a result, penicillin is rarely used empirically, and in only limited situations used as directed therapy.

Sidebar: Resistance to penicillin in many Streptococcal species has not been so easy. Why is that? In short, expressing bacterial resistance mechanisms is at a cost to a bacteria’s own fitness. The parallel in our lives would be: Who is likely to live longer? The man/woman who works an 80 hour/week job, or the one who works the same job but works 40 hours/week? In some bacterial species the cost is greater than others (more on bacterial fitness in future blogs).

Refocus: Why is this important? Consider the following. The most common cause of community acquired pneumonia (CAP) is Streptococcus pneumoniae. Previously if a S. pneumoniae causing pneumonia in a patient was tested by a clinical microbiology lab and found to have a minimum inhibitory concentration of >= 0.12mcg/ml, that was interpreted as resistant. In other words, if penicillin was used to treat this patient, the likelihood of a good clinical outcome was low. Over time, it has been shown in several clinical studies, that this breakpoint concentration for resistance was too conservative, and recently a resistance breakpoint of >= 8mcg/ml was endorsed as appropriate for S. pneumoniae non-meningitis disease. In doing so the resistance rate for penicillin in S. pneumoniae fell dramatically. For example, in 2007 at UPMC Presbyterian, resistance fell from 25% to 2%.

How will practice change as a result? The Current guidelines for CAP don’t include penicillin as an empiric therapy option, as these breakpoints were changed after the publication of the most recent CAP guidelines. In future guidelines, penicillin (plus an additional agent for Hemophilus influenzae and atypical organisms) will be the new recommended empiric therapy in patients with CAP. What is old is new again indeed.

What’s New?

A recent study published in the New England Journal of Medicine details a prospective study where pregnant mothers received either the influenza vaccine or control. Mothers and babies were assessed by investigators over a 17 month period. The complete results can be found here http://content.nejm.org/cgi/content/full/NEJMoa0708630?query=TOC

In summary, the results indicated a 63% reduction in proven influenza illness in babies (up to 6 months of age) of mothers that received the influenza vaccine while pregnant versus the control group. Additionally, secondary outcomes were favorable in this arm as well (including clinic visits, any respiratory illness with fever, etc.).

How can we improve the lives of our patients with this knowledge?

For pharmacists in all health-care settings, we can encourage pregnant women to get the influenza vaccine – not only for their benefit, but for the benefit of their unborn child.

Consider the following scenario: You are a licensed pharmacist who is certified to administer vaccines and are currently spending time at a local community pharmacy immunizing patients against the influenza virus. An elderly gentleman walks up to you and says “I usually get the flu shot, but I’m not now – did you hear it doesn’t work?”

What is he talking about? How do you respond?

There have been a number of studies some recent, some a number of years old, that together call into question the benefit of the influenza vaccine in the elderly. Here is a straightforward review to help you educate your patients when you encounter the previously described situation. The information below will get some media attention and I expect the lay public to largely misunderstand what is being said.

What you need to know (a summary):

1. A recent study published in the Lancet identifies a significant difference in the health, well being, and frailty of elderly patients that get the flu shot versus those that don’t. This difference equates to a bias when comparing the outcomes of these groups without controlling for these confounding factors. This has led several studies in the past to overestimate the effect of the flu shot in the elderly
2. A study published in 2005 found that although the number of elderly receiving the flu shot more than tripled over the years 1980 to 2001, the death rate did not change
3. In the mid ‘90s JAMA published findings that in the elderly 60-69 years old, the vaccine prevented influenza about 57% of the time compared to those ≥ 70 years old influenza was prevented only 23% of the time
4. Plausibility – At an annual vaccine conference, researchers recently presented findings that elderly patients require 4 times the amount of influenza antigens to elicit the same immune response as their younger aged peers

How should we interpret these findings?

1. Immune senescence (waning immune system) leading to a less than ideal immune response to exposed antigens in the elderly is well known
2. It is likely that previous studies have overestimated the efficacy of the influenza vaccine in the elderly, particularly those over 70. Before any further definitive recommendations can be made, further studies controlling for recently identified confounders needs to be conducted. An editorial identifying the appropriate methodology for this future study has already been published

Most importantly, what should we tell our patients?

1. The Centers for Disease Control and Prevention (CDC) guidelines for those who should receive the flu shot will remain the same
2. New studies show that the flu shot might not be as beneficial to the elderly as previously thought, but that doesn’t mean it doesn’t work
3. The elderly should continue to receive the flu shot – some protection is better than none at all

From the present day perspective, the year 1918 is a decade shy of a century ago, so how could these researchers possibly hope to answer this question? The answer: autopsy lung tissue specimens from 58 decedents infected during the 1918 Influenza pandemic. Jackpot!! The scientists of that time had the good sense to save these tissues for another time – now. The study is to be published in the Journal of Infectious Diseases and is available on-line ahead of print and accessible to you through the HSLS website (first author Morens, David M.) The authors found “The histologic spectrum observed in the cases corresponded to the characteristic pathology of bacterial pneumonia . . . . .” consistent with pneumococcal (another term for Streptococcus pneumoniae), streptococcal, and staphylococcal pneumonia. The clincher: according to the authors, bacteria were commonly seen in “massive numbers”.

Their conclusion, as suggested by this blog's title? It was pandemic influenza that caused severe illness, but it was the subsequent bacterial pneumonia that ultimately delivered the coup de grâce. Bacterial pneumonia after viral pneumonia is common today, too. The difference? 1918 was a time before vaccines, and especially, before antibiotics.

What are the implications for us now in the 21st century? It may be neurominidase inhibitors such as oseltamivir (Tamiflu) that will help to prevent the spread of the next pandemic, but antibiotics such as azithromycin will be used to make sure that a secondary bacterial infection won’t lead to the carnage seen early in the 20th century. Stockpiling of antibiotics for this purpose is already underway. We as pharmacists will be on the front lines of this battle if and when it comes.

The infectious diseases blog is designed to complement the course goals of Pharmacotherapy of Infectious Diseases I and II. This is done by fostering the students’ critical thinking skills and infectious diseases knowledge by augmenting the existing coursework with emerging reports/data posted on the blog which directly impact the practice of pharmacy. The blog will provide students the opportunity to post comments and spur discussion between faculty and student, and among students themselves. Lastly, the blog is consistent with the School of Pharmacy’s Mission in using innovation in education and patient care.