Category Archives: Allergy and Immunology

Can Pill Color Prompt a “Nocebo” Response?

What’s the opposite of a placebo? An active drug, of course. But what’s the opposite of a placebo response? That would be a “nocebo” response, in which placebos produce adverse side effects.
 
“It’s somewhat hypothetical, but you can imagine that if somebody feels they will get better, they will get better, and if they feel that they’re taking something that’s not good for them, they might get worse,” according to Dr. Allan Krumholz, professor of neurology and director of the Maryland Epilepsy Center, Baltimore.

Image courtesy of Dr. Tricia Y. Ting

Pill color and appearance have been identified as a potential source of “nocebo” response, and differences in appearance between brand-name and generic drugs have been postulated to explain why some patients experience increased adverse events when they switch from brand-name to generics.

In response to this growing concern, in August 2010 the Food and Drug Administration solicited proposals for bioequivalence studies of the impact of switching from brand-name antiepileptic drug lamotrigine (Lamictal) to generic among patients with epilepsy in the outpatient setting.

This is a new way of conducting such trials. “Pharmacokinetics trials across all areas of medicine have traditionally been highly controlled single-dose studies in healthy volunteers dosed in the laboratory setting,” said lead investigator Dr. Tricia Y. Ting, a neurologist who works with Dr. Krumholz at the UMD epilepsy center.

Because the brand-name Lamictal and its generic counterparts look very different, the investigators decided to over-encapsulate the pills with identical coverings in order to “blind” the patients to which formulation they were taking.

But in order to do that, they first needed to determine whether the color of the pill would impact the patients’ perception of safety and efficacy. A group of 80 adult epilepsy patients were shown standard AA size capsules in five “global colors” (white, yellow, gray, caramel, maroon) and asked to select any color(s) considered “unacceptable” and to rank their preferences.

More patients deemed gray, caramel and maroon colors “unacceptable” (21%, 19%, and 20%, respectively) compared with the white and yellow (5% and 4%, respectively). There was a clear preference for white and yellow pills over the other, darker colors, without much difference between white and yellow.

But, there were patients who selected maroon as their “preferred” color. “Some people didn’t have any preference. Some had a very strong preference. One patient, an artist, liked the darker colors. It was different for different people,” noted Dr. Karen M. Aquino, a neurology fellow who worked on the nocebo study.

So what pill color will the bioequivalence study use? “To optimize drug adherence, white colored capsules will be used for over-encapsulation,” Dr. Ting wrote in her poster, which was presented at the American Epilepsy Society’s annual meeting in Baltimore. Dr. Krumholz and Dr. Aquino presented the pill color preference data in a separate poster at the meeting. The bioequivalence results are expected in 2013.

-Miriam E. Tucker (@MiriamETucker on Twitter)

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Approved or not Approved? That is a Good Question.

In a move last month that apparently took at least two device manufacturers completely by surprise, one center of the Food and Drug Administration recommended against an intended use of their products, despite the products’ approval and licensure by another FDA center.

PharmaJet's Stratis is used to vaccinate a Cambodian child against measles. Photo courtesy of Heather Potters.

Recent jet injector models, including Bioject’s ZetaJet and Biojector 2000 and PharmaJet’s Stratis, were approved and licensed by the FDA’s Center for Devices and Radiological Health (CDRH) as needle-free alternatives for injecting vaccines and injectable medications. Both companies had been marketing their devices for influenza immunization in the current flu season.

On October 26th, the FDA’s Center for Biologics Evaluation and Research (CBER) issued a notice  advising healthcare professionals that inactivated influenza vaccines should be administered only with a sterile needle and syringe. The reason: “Safety and effectiveness information that would support labeling inactivated influenza vaccines for delivery by jet injector have not been submitted to FDA.” However, CBER said, individuals who have already received a flu vaccine with a jet injector do not need to be revaccinated.

Currently, only the measles-mumps-rubella vaccine is approved and specifically labeled for administration by jet injector.

So what’s the concern with influenza vaccine? “A jet injector subjects the vaccine to a different pressure than it would receive during administration by sterile needle and syringe and as a result the effectiveness and the safety profile of the injected vaccine may be altered,” according to the CBER document.

Evidently this information had not been previously communicated to the manufacturers. “We were provided no notice by FDA of any concerns about Jet Injectors or FDA’s statement. To our knowledge, no other needle-free injection manufacturer received notice or an opportunity to discuss this matter with FDA,” PharmaJet said in a statement.

Bioject’s President and CEO Ralph Makar was similarly taken aback by the FDA notice. “The FDA communication on the use of jet injectors with influenza vaccines was surprising given that Bioject’s Needle-Free Injection Devices…are both FDA 510(k) cleared with indications for use that describe their use in delivery of subcutaneous or intramuscular injections of vaccines and other injectable drugs,” he said in a statement.

In a public comment at the October meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices, PharmaJet Inc’s chairman Heather Potters said, “Last year we scaled up to provide several hundred thousand syringes, and this season we were expecting to sell several million. Now, our domestic sales have virtually stopped, except for [investigational trials].”

The companies are expected to meet with the FDA in early January to work this out. According to Mr. Makar, “We are looking into the matter to better understand the situation and the FDA’s concerns. A number of Bioject’s Needle-Free Injection devices have been on the market for many years and we are committed to resolving this matter with the FDA in a timely manner.”

-Miriam E. Tucker (@MiriamETucker on Twitter)

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Antibiotic Smarts Week Is Here

Today the Centers for Disease Control and Prevention kicked off its third annual “Get Smart About Antibiotics Week”, a time to reflect on practical ways that clinicians and health consumers can reduce the rates of antibotic resistance.

One of the posters for this year's campaign. Image Courtesy CDC.

The campaign’s three main goal are to promote adherence to appropriate prescribing guidelines among providers, decrease demand for antibiotics for viral upper respiratory infections among healthy adults and parents of young children, and increase adherence to prescribed antibiotics for upper respiratory infections.

A wide variety of campaign-related free media are available for clinicians to use in their practices, from printable brochures about proper antibitoic use and one-page information sheets to posters and treatment guidelines for upper respiratory tract infections, one geared for adults and one for children. A number of related podcasts and videos geared to health consumers are also available.

The effort’s home page can be accessed here.  Happy campaigning!

— Doug Brunk (on Twitter@dougbrunk)

Image courtesy Centers for Disease Control and Prevention.

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Breakfast in Bed, Anyone?

What do beds and pancakes have in common?

Nothin' says lovin' like dust mites from from the... frying pan? Photo by Flickr Creative Commons user Kalavinka

A: Romantic interlude

B: Snuggly Sunday treat

C: Wonderfully considerate partner

D: Potentially lethal mites

Answer:  All of the above

If you’re lucky in love, you get some romance along with your hot pancakes, propped up on your comfy mattress and fluffy pillows.

If you’re not so lucky, you suck in a lungful of Dermatophagoides pteronyssinus from your comforter and slug down a syrup-coated helping of its wheat-loving cousin, Dermatophagoides farina. And if your immune system is easily triggered, this relaxed repast can turn into a choking, wheezing trip to the hospital.

The tiny (300 micron), translucent house dust mite frequently haunts human beds, thoughtfully cleaning up mold, fungi, bacteria, pollen, your dead skin cells, and maybe that other white sock you lost a couple months ago.

Dermatophagoides pteronyssinus - a species of house dust mite. Photo by Flickr Creative Commons user Giles San Martin

Because of their tiny size and adaptive nature, these guys traveled with us from our damp, dark caveman homes to our modern hang outs and creature comforts:  beds, blankets, sofas, rugs, and cuddly stuffed animals.

For most of us, house dust mites cause no problem. They’re so tiny we can’t see them. They don’t sting or bite. And even if 100 were creeping up your leg – which they will probably do tonight – you would never know.

But unfortunately, they can seriously bug people with atopy. It’s not the mite per se, but its numerous droppings that cause issues among the allergic.  Inside those tiny poo balls are bits of undigested food and the digestive enzymes meant to break them down. All it takes is a breath of air – or a dip in pancake batter – for the “stuff” to melt away,  activating these enzymes.

Inhalation reactions start when the molecules come into contact with lung epithelium. Scavenger cells get the inflammatory process up and running, aggravating asthma and other allergic reactions, like atopic dermatitis, allergic rhinitis, conjunctivitis, and otitis media.

Pancake syndrome is a variation of the inhalation reaction. Whenever cooks use mite-infested flour, there is potential for danger. The medical literature contains case reports and series of both children and adults who experienced an anaphylactic reaction after eating mite-infested wheat-flour based foods. The reactions varied from mild to lethal.

In all cases, the flour used was replete with dust mites of several species – and full of the cell-destroying Der enzyme, cysteine protease. Among its many talents: direct damage to airway epithelium; destruction of the body’s epithelial tissue damage defense system; disruption of intercellular junctions; and of course, stimulating those pesky proinflammatory mediators.

Infested flour is more likely to be found in temperate, humid areas, and in poorly stored wheat flour or flour-based mixes – or products that have been opened for a long period and never used. In 2009, the World Allergy Organization published a dust mite oral anaphylaxis paper, suggesting that all grain flours be stored in airtight containers in the refrigerator or freezer.

So the next time a half-empty box of pancake mix gets you in the mood for some snuggly breakfast in bed – try switching to eggs. – Michele G. Sullivan

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Immunizing in the Inpatient Setting

August is National Immunization Awareness month, which means back-to-school physicals and likely a new round of pseudoscience stirred up by the antivaccine crowd. Perhaps some have forgotten the consequences of failing to vaccinate our children.

Credit: National Institutes of Health

Pediatricians and family practitioners haven’t, and based on new data presented at the Pediatric Hospital Medicine 2011 meeting in Kansas City, nor have their hospitalist colleagues.The Children’s Hospital of Wisconsin in Milwaukee has developed a process to identify and immunize hospitalized children prior to discharge. Milwaukee County lags significantly behind national and Wisconsin child-immunization rates, with just 47% of 2-year-old inpatients fully immunized, compared with about 83% in all of Wisconsin and 81% nationally, Dr. Anjali Sharma explained at the meeting.

“We did the study because we felt an obligation,” she said.  “With so many patients that are obviously not able to get it done at their primary physicians for whatever reason, we really wanted to get them immunized and see if there are other avenues to eliminate these missed opportunities.”

The four-pronged process includes printing an immunization record from the Wisconsin Immunization Registry (WIR) at admission, having nurses screen for vaccine contraindications using the CDC tool, educating physicians about the importance of ordering immunizations and true immunization contradictions, and developing a standardized order set to immunize children at discharge.

During the prospective, pilot project test period, 414 children were admitted to the hospital, with 142 eligible for vaccines.

Only 13, or 9%, of these children were fully immunized, leaving 129 patients with missed vaccine opportunities, Dr. Sharma said.

Moreover, 60% of the 129 patients remained not fully immunized 6 months after discharge.

“It’s obvious we want to get more kids immunized in the hospital because those really, truly were missed opportunities because they didn’t get immunized later,” she said.

Contrary to popular belief, true contradictions to immunization occurred in just 5% of cases. Other reasons for the missed opportunities include WIR records not being reviewed, screening tools going uncompleted because of nursing disinterest and physician error.

Since the study, Children’s Hospital has begun a 5-year immunization initiative to address this issue.  Changes include linking hospital electronic health records to the WIR, process improvement, and education of staff at all levels, according to the authors of the study, led by pediatric hospitalist Dr. Angela Bier at the Medical College of Wisconsin, also in Milwaukee.

— By Patrice Wendling

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The Little Ant With the Big Bite

Just speaking with Dr. Ronald Rapini during the summer meeting of the American Academy of Dermatology  is enough to make you itch. That’s how good he is at describing the vicious attack of the fire ant – as it bites and stings its way northward from its Southern roots.

A native of South America, this aggressive invader established the first Fire Ant Town around Mobile, Ala., in the early 1900s. Rumor has it that the little buggers were stowaways on steamers. Apparently they found American soil so friable (and American flesh so tender) that they have engaged in a relentless northern march, traveling first throughout the southeast and now up both the Eastern and Western seaboards.

Fire Ant

Fire ants belong to the same species as wasps and bees. (Photo courtesy Agricultural Research Service, USDA)

Fire ants sport a chillingly descriptive Greek name – Solenopsis invecta, “Unvanquished Channel-Faced.” I leave it to you to decide if the imported red fire ant is “channel-faced,”  but I defy you to deny that it is unvanquished.

These are a species of the Hymenoptera, the insect order that includes wasps and bees, and they share some basic characteristics. Unlike their cousins, fire ants are only winged during the spring, when the await Eros’ call to fly from their nests in a mating frenzy – after which their diaphanous wings drop away and they build ever-more-complicated colonies that can spread throughout entire fields.

They also adhere to their order’s inclination to live in large, hierarchical societies arranged around a queen, with armies of workers bent on aggressive nest defense — much to the dismay of bumbling human feet.

If you invade their space, the ants swarm out with a
double-ended defense, Dr. Rapini, chair of dermatology at the University of Texas Medical School, Houston, said in a video interview.

“Unlike most ants, which just bite you, these guys bite with their huge jaws and then pivot around and sting you,” with a venom filled dagger.

The resulting wounds are painful, itchy, and full of pus.  Although familiar to Southern physicians, who have seen the problem for years, Northerners are just coming to grips with these tiny purveyors of pustular pain.

“Sometimes doctors will even get a biopsy on this because they’ve never seen it before,” Dr. Rapini said.

Because a fire ant bite/sting feels pretty much like someone burning you with a lit cigarette, most  humans are cognizant enough to run hysterically away from a fire ant encounter, doing the “fire ant dance” to shake the critters off their legs and shoes and out of their trousers. But like drinking and driving, drinking and fire ant hills are not a good mix, Dr. Rapini said.

An inebriated man fell asleep on a fire ant hill with dire consequences. (Photo courtesy of Dr. Ronald Rapini)

“My worst case was a guy who got drunk and passed out on a fire ant hill and came in with hundreds of stings,” he said. The patient wound up in the hospital, desperately ill with a bacterial superinfection; treating him required both antibiotics and high-potency corticosteroids.

There have even been reports of fire-ant deaths.

For most folks, though, the bites are painful, but few. A prescription-strength corticosteroid cream will at least help get patients through the worst stages. “It basically is a self-limiting issue; the bites just go away over a week or two,” Dr. Rapini said. “You really have to try not to scratch, though. That’ll make a scab. And pickers get scars.”

And by the way, humans aren’t the only creatures to suffer at the jaws and stingers of fire ants. They can cause terrible injuries in reclining baby animals.

Pets can also be at risk.

As are, apparently  cute little caterpillars and tweeting birdies.

— By Michele G. Sullivan (on Twitter @MGSullivan)

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Medical Errors Hurt Doctors, Too

Doctors and nurses make mistakes, some of which hurt patients. To err is human. In fact, that’s the name of a 2000 Institute of Medicine report aiming to decrease errors in health care.

Calcium chloride photo by Markus Brunner (Wikimedia Commons)

The Institute for Safe Medication Practices (ISMP), a non-profit that focuses the bulk of its work on improving patient safety, also recognizes that a patient injured by a medication error isn’t the only one hurting after the mistake. A recent newsletter and press release draw attention to the so-called “second victims” of medication errors — the healthcare workers who are involved in the error.

Healthcare workers may react with feelings of sadness, fear, anger, and shame, and be haunted by the incident. They may lose confidence, become depressed, and even develop PTSD-like symptoms.

A case in point: Kimberly Hiatt, a pediatric critical care nurse with 27 years of experience, made a mathematical error that resulted in an overdose of calcium chloride in a fragile infant. The baby died. Hiatt’s life went into a tailspin. She felt consumed by guilt. She lost her job and, despite obtaining extra training, she was unable to find work. Seven months later, she committed suicide in April 2011.

The ISMP says a culture of silence and lack of support surrounds medication errors in healthcare, and it points healthcare workers to resources to change that culture. For example, you can watch a free webinar about the second victims of medical error, produced by the Texas Medical Institute of Technology. A toolkit for building a support program for clinicians and staff is available from the Medically Induced Trauma Support Services.

If you’re a healthcare worker, what’s it like at your institution when medication errors happen? Does anyone ever hear about them? Are there mechanisms in place to learn from mistakes? Is there any structural support for healthcare workers who make a mistake?

Have you ever had to deal with a medication error or other medical error of your own? How did you cope?

Leave a comment and let us know.

—Sherry Boschert (on Twitter @sherryboschert)

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