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Sunday, January 31, 2016

During flu season we have many requests for Tamiflu (oseltamivir) because of flu exposure or disease. I have rarely complied with these requests, though in recent years more often due to the powers that set the guidelines recommending it more. It is more common in my experience to hear negative feedback about side effects than it is to see patients get better faster. (Note: this is a very biased view, since those who are better would not call, but since so many call with side effects it seems fair to say I don't like the drug.)
photo source: Shutterstock


I am not alone in my dislike of Tamiflu. I follow a listserv of pediatricians around the country and many share my views. A recent topic thread on treatment of flu has peaked my interest. One doctor suggested watching a TED Talk by Dr. Ben Goldacre: What doctor's don't know about the drugs they prescribe.  Dr. Goldacre starts talking about Tamiflu specifically about 10:10, but the entire lecture is done in an entertaining and informative manner if you have the time.

I feel deceived. When I practice medicine, I follow standard recommendations and guidelines that are based on peer reviewed articles and data. The question is, what important data is left out? There is a movement to solve this problem of unpublished studies. You can see updates at the Tamiflu Campaign of the British Medical Journal.

Back to influenza treatment...


First, current influenza treatment guidelines regarding the use of antivirals: 


The current guidelines basically say every child should be considered a candidate for an antiviral treatment. I understand the reasoning behind the first two conditions of antiviral use (except that studies don't really support even those indications), but I am very confused about the third highlighted below.

(from http://aapnews.aappublications.org/content/early/2013/09/02/aapnews.20130902-1)

ANTIVIRALS CONTINUE TO BE IMPORTANT IN THE CONTROL OF INFLUENZA.
Treatment should be offered for:
  • any child hospitalized with presumed influenza or with severe, complicated or progressive illness attributable to influenza, regardless of influenza immunization status; and
  • influenza infection of any severity in children at high risk of complications of influenza.
Treatment should be considered for:
  • any otherwise healthy child with influenza infection for whom a decrease in duration of clinical symptoms is felt to be warranted by his or her pediatrician; the greatest impact on outcome will occur if treatment can be initiated within 48 hours of illness onset.

Then look at what a search for "unpublished tamiflu trials" shows.

For those of you unfamiliar with the Cochrane group, I need to take a quick sideline. They are a well respected group that reviews all the studies within certain parameters on one topic to evaluate the overall findings of several independent studies. 

From the Cochrane Group: A review of unpublished regulatory information from trials of neuraminidase inhibitors (Tamiflu - oseltamivir and Relenza - zanamivir) for influenza. These results are from a review of published and unpublished studies that they could find. From the abstract: "The authors have been unable to obtain the full set of clinical study reports or obtain verification of data from the manufacturer of oseltamivir (Roche) despite five requests between June 2010 and February 2011. No substantial comments were made by Roche on the protocol of our Cochrane Review which has been publicly available since December 2010. 

They found several problems with Tamiflu from the studies they were able to review:

  • Drug manufacturers sponsored the trials, leading to publication and reporting biases. One of the authors reported that 60% of the data was never published. This is over half of the research, and I suspect it didn't support use of the medicine (remember the company that benefits from selling the medicine was doing the trials...)
  • There was no decrease in hospitalization rate for influenza in people treated with Tamiflu.
  • There was not enough evidence of prevention of complications from influenza. Design of the trials (again by the people who make the drug) did not report the prevention of complications from influenza, such as secondary infections.
  • There is not evidence in the trials to support that Tamiflu reduces spread of the virus. One of the main reasons people request the medication is after exposure to prevent illness! (Note: this might have changed because the indications on the package insert now say it can be used to prevent illness in those over 1 year of age and they were previously not allowed to mention prophylaxis.) 
  • Tamiflu reduced symptoms by 21 hours. Yep. Less than one day of fewer symptoms. For the cost of the drug and the potential side effects, is feeling sick for 1 day less really worth it? 
  • There was a decreased rate of being diagnosed with influenza in those randomized to get Tamiflu, probably due to an altered antibody response. The authors suspect a body becomes less able to make its own antibodies against influenza when taking Tamiflu. 
  • Side effects were not well documented.

A review study done in children exclusively Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials focused on treatment of disease and prevention of illness after exposure. Findings included:

  • Symptom duration decreased between 0.5 and 1.5 days, but only significantly reduced symptoms in 2 of 4 trials. That means in 2 of 4 trials there was no significant reduction in symptoms.
  • Prophylaxis after exposure decreased incidence by 8% of symptomatic influenza. This means for every 13 people given Tamiflu to prevent disease, one case will be prevented. Not great odds.
  • Treatment was not associated with an overall decrease in antibiotic use, suggesting it did not alter the complication of bacterial secondary infections.
  • Tamiflu was associated with in increased risk of vomiting. About 1 in 20 children treated with Tamiflu had an increased risk of vomiting over the baseline vomiting due to influenza.
  • There was little effect on the number of asthma exacerbations or ear infections by treating influenza with Tamiflu.

So what do I recommend during the cold and flu season?



  1. Get vaccinated! The influenza vaccines have been shown to help prevent influenza and are very well tolerated with few side effects. If you or your children are due for other vaccines, be sure to get caught up.
  2. If you get sick, stay home until you're fever free without the use of a fever reducer for at least 24 hours! Don't spread the illness to others by going to work or school. The influenza virus is spread for several days, starting the day before your symptoms start until 5-7 days after symptoms start-- kids may be contagious for even longer. You are most contagious the days you have a fever.
  3. Wash hands well and frequently. If you can't use soap and water, use hand sanitizer.
  4. Cover your cough and sneeze with your elbow or a tissue.
  5. Avoid close contact with people who are sick. But remember that people spread the virus before they feel the first symptoms, so anyone is a potential culprit!
  6. Don't share food, drinks, or towels (such as after brushing teeth to wipe your mouth) with others. 
  7. Don't touch your eyes, nose, and mouth -- these are the portals for germs to get into your body. 
  8. Keep infants away from large crowds during the sick season.
  9. Frequently clean objects that get a lot of touches, such as keyboards, phones, doorknobs, refrigerator handle, etc.
  10. Avoid smoke. It irritates the airway and makes it easier to get sick.
  11. Remember that many germs make us sick during the flu season. Just because you've been sick once doesn't mean you won't catch the next bug that comes around. Use precautions all year long!
Because the guidelines recommend Tamiflu as above, I will probably be forced to prescribe it by worried parents who hope that their kids will feel better. (You've heard of defensive medicine, right?) 

Influenza is a miserable illness. The key is prevention. I've had my vaccine, how about you? 


Further Reading:

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children: A link is available to the full text of the study by T Jefferson, MA Jones, P Doshi, CB Del Mar, CJ Heneghan, R Hama, and MJ Thompson.

Update 2016:


There continues to be a lot of confusion about unpublished studies. Investigators have documented their discussions with the maker of Tamiflu on Tamiflu correspondence with Roche.

Recent studies have tried to compile all that is known about how oseltamivir works:
Results from this study include:
  • In the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.7 hours, 29 hours in children.
  • There was no difference in rates of admission to hospital between treatment groups in both adults and children.
  • Oseltamivir relieves symptoms in otherwise healthy children but has no effect on children with asthma who have influenza-like illness.
  • Oseltamivir had no significant effect on admissions to the hospital.
  • Oseltamivir causes gastrointestinal disturbances in both prophylaxis and treatment roles. In prophylaxis, it caused headaches, renal events (especially decreased creatinine clearance), and psychiatric effects. 















Saturday, January 16, 2016

Antibiotic Allergy or Just a Rash?

During the winter months more people get sick, so more people are treated with antibiotics. While antibiotics can help treat bacterial infections, they do carry risks. One of those risks is an allergic reaction. This is one of the reasons pediatricians avoid using antibiotics liberally. Most of the time our bodies can fight off the germs that cause illness and antibiotics don't help treat viruses at all.

When someone is on a medicine and they develop a rash it can sometimes be hard to sort out if symptoms are part of the illness, a non-allergic drug reaction, or an allergic reaction. There are many people who had a rash while taking an antibiotic as a child and were told that they are allergic to that antibiotic, but really aren't. Unfortunately this can lead to more expensive and broader-range antibiotics being used inappropriately and unnecessarily.

About 2% of prescription medications (not just antibiotics) cause a "drug rash". The rash usually begins after being on the medicine for over a week (earlier if there was previous exposure to the medicine), and sometimes even after stopping the medicine. It can look different in different people. Some get pink splotchy areas that whiten (blanch) with touch. Others get target-like spots, called Erythema Multiforme. Often the rash seems to worsen before it improves, whether or not the medicine is stopped. Skin can peel in later stages. It can itch but doesn't have to. Some people have mild fever with these symptoms. In adults this type of rash is often a sign of allergic reaction, but in kids a rash is most often a viral rash - meaning they have a virus that causes a rash but they happen to be on an antibiotic (or other medicine). This is why diagnosing allergy versus drug reaction is tricky. These symptoms can mean allergy to the drug, but (especially in kids) is often just a symptom of a virus (or some bacteria, such as Strep or Mycoplasma).

Up to 10% of children taking a penicillin antibiotic (which includes the commonly used amoxicillin and augmentin) develop a rash starting on day 7 of the treatment. (It can be earlier in people who have had the antibiotic previously.) This rash tends to start on the trunk, looks like pink splotches that can grow and darken before fading. It does not involve difficulty breathing, swelling of the face or airway, or severe itching. Because of this reaction many people live their life thinking they have an allergy to penicillin, even though many of them don't. 

Amoxicillin rash after 17th dose (about the 8th day). Photo source: By Skoch3 (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY-SA 4.0-3.0-2.5-2.0-1.0 (http://creativecommons.org/licenses/by-sa/4.0-3.0-2.5-2.0-1.0)], via Wikimedia Commons
Same child, 8 hours after the above photo. Photo source: By Skoch3 (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY-SA 4.0-3.0-2.5-2.0-1.0 (http://creativecommons.org/licenses/by-sa/4.0-3.0-2.5-2.0-1.0)], via Wikimedia Commons


Why does this happen? We don't know for sure. But it can cause a very significant rash, especially with the virus that causes mono.

Up to 80 -90 % of people who have mono develop a rash if they are treated with a penicillin antibiotic (like amoxicillin). This is common since symptoms of Strep throat and mono are very similar, and penicillins are the drug of choice for Strep throat. Some people with mono have a false positive test for Strep throat, meaning they do not have Strep but the test is positive. This is why it is very important for the medical clinician to take a careful history of symptoms and do an exam, even with "classic" Strep symptoms. (If I had a dollar for every parent who says the symptoms are just like all her kids when they get Strep, can't I just call it in...) Always be sure to get a Strep test and full exam to evaluate if it is really Strep or possibly mono. Blood tests for mono can be ordered if clinically indicated. Never treat a sore throat without a full evaluation.

Amoxicillin rash that developed several days after starting amoxicillin with mono. Image from Ă“nodi-Nagy et al. Allergy, Asthma & Clinical Immunology 2015 11:1   doi:10.1186/1710-1492-11-1



How do we know if it's a real allergy? 


Doctors will take a careful history of all symptoms of the illness, the timing of when the rash developed during the illness and when the medicine was given. If it is a classic viral rash, nothing further needs to be done. If there are symptoms (see below) that help identify a true allergy and make a clear diagnosis, then avoidance of that medication should be done. Be sure all your doctors and pharmacists know of this allergy. If it is not clear then further evaluation can be done. Allergists can do skin testing to see if there is a penicillin allergy, but most antibiotics do not have testing available so an oral challenge (in a controlled setting) is used if there were no clear allergy symptoms with a rash.

Mild to moderate allergic reactions can have the following symptoms:
  • Hives (raised, extremely itchy spots that come and go over a period of hours)
  • Tissue swelling under the skin, often around the face (also known as angioedema)
  • Trouble breathing, coughing, and wheezing
Anaphylaxis is a more serious allergic reaction and can include:
  • Difficulty breathing or wheezing
  • Swelling of the face, tongue, throat, lips, and airway
  • Dizziness
  • Loss of consciousness
  • Shock
  • Death

Final Take Away


As you can see, rashes that develop while on medications can be quite a conundrum. If one develops, be sure to get in touch with your doctor. We usually cannot diagnose rashes over the phone, so an appointment may be necessary.



Thank you to Kressly Pediatrics for posting a comment on Twitter (@KresslyPeds) about drug reactions to give me the idea for this blog!