Postinfectious Cough

I am not a huge baseball fan to begin with, and when I am, I route for the Nationals.  Thus, I pay little attention to the New York Yankees, and was not aware that Yankee player Mark Teixeira had been suffering with a cough for the past month until it the story from the New York Times came through one of my Twitter feeds. According to the story:
"Mark Teixeira had a battery of tests performed Wednesday to determine the nature of his violent and persistent cough, and he received good news. Teixeira, who has been wracked by the cough for about a month, said he was found to have nothing more serious than severe congestion in his bronchial passageways." 
Mr. Teixeira was prescribed prednisone (not something I would recommend for this) and is expected to recover soon. In addition, the doctors at New York-Presbyterian/Columbia hospital in Manhattan performed a CT scan, a lung function tests, blood tests and cultures during their work up (though I am sure the Yankees can afford this). The Times does not mention the diagnosis other than to say that the baseball player had "severe inflammation in my bronchial passageways."

I blog about this because this is one of the most common things I see in the primary care setting, it is often misunderstood and therefore misdiagnosed, it is very easily treated and there is virtually no research on this disease.

Mr. Teixeira likely has what is known as postinfectious cough. Here's the typical patient presentation:
Young healthy patient gets a typical upper respiratory tract infection (URI): cough and congestion, headache, feels ill and low grade fever. URI resolves in a matter of days, but there is a persistent cough that is getting worse, and won't go away.  Cough is usually worse at night, and the patient can't exercise because it makes them cough. On occasion the cough is so bad that the patient is winded easily and sometimes the patient thinks they may be wheezing, though they have no history of asthma.

According to the American College of Chest Physician which published evidence-based clinical practice guidelines back in 2008, the diagnosis of post infectious cough should be considered when a patient complains of cough that has been present following symptoms of an acute respiratory infection for at least 3 weeks,but not more than 8 weeks.  And while the cause of the postinfectious cough is not known, it has been thought to be due to the extensive damage of cells lining the lung and widespread airway iinflammation of the upper and/or lower airways. The good news is that this usually goes away by itself, the bad news is that it can take weeks or even months, and can be quite disruptive to patients lives; desk jockeys and baseball players alike.

To me one of the most incredible things about this illness is the lack of data on effective treatments. The ACCP review cited above did an extensive review of the literature and found very few studies that looked which treatments worked best. Given the lack of data, here is my take on the appropriate diagnosis and treatment:

Diagnosis can be made without an extensive workup when the clinical presentation is consistent with that described above and there are no other complicating factors that would indicate other possibilities. A chest X-ray may be all that is necessary to rule out any underlying severe disease and is reasonable in a patient who has been coughing for more than two weeks.

Since symptoms are caused primarily by inflammation and hyperresponsiveness/bronchoconstriction in the lungs (which is what we see in asthma), then treatment is likely best with something that treats both inflammation and bronchoconstriction in the lungs, such as an inhaled corticosteroid/long-acting beta agonist like Advair (which is commonly used in asthma).  Of note, Advair (or other ICS/LABA combinations) have not been approved by the FDA for the treatment postinfectious cough and there is no data on the use of ICS/LABA's for the treatment of postinfectious cough.  However, this is a common sense approach to the problem based on what we know about the cause, and from clinical experience I can tell you this approach works remarkably well.  Use of Advair for postinfectious cough may be the single most common off-label use of any prescription product.
There are two additional important points.  First, since inflammation can persist for weeks, it is important that Advair be used for at least 4 weeks.  If stopped too soon, before inflammation has completely resolved, symptoms may return.  This is very important, because primary care physicians who decide to use ICS/LABA inhalers for postinfectious cough may give patients a medication sample rather than a prescription.  Though the drug companies that make these products used to make samples with a month's supply of medication, most inhaler samples today have only 1-2 weeks of therapy.  Secondly, if symptoms have resolved and the patient has taken the inhaler for 4-6 weeks, the patient can safely stop the inhaler.  If symptoms return, the patient should be brought back for pulmonary function testing as this may be a new presentation of asthma.

Good Bye Primatene Mist

As reported today by the Washington Post, Primatene Mist’s days are numbered. The FDA announced today that "the only over-the-counter asthma inhaler sold in the United States will no longer be available next year as part of an international agreement to stop the use of substances that damage the environment."

This is because, similar to the old albuterol meter dose inhalers, Primatene Mist uses a CFC as a propellant which is harmful to the environment. I blogged about this previously (see FDA Announces End for CFC-Propelled Inhalers Asthma inhalers and More on Asthma Inhalers ).

However, the loss of Primatene Mist is a good thing in my opinion. Primatene Mist is epinephrine. It is a bronchodilator, which is why it relieves the symptoms of asthma. However, it is quite dangerous, especially without a prescription. First, it is not just a beta 2 agonist like albuterol which works almost exclusively on beta receptors in the lungs. It also aftects beta 1 receptors in the heart and alpha receptors in the blood vessels. The primary use of epinephrine is medicine today is to give it to patients who are a risk of immediate death in order to restart their hearts. In addition, having any bronchodilator, even albuterol, over the counter, is a bad thing. We know that increased albuterol use is associated with increased ER visits, hospitalizations and even death. But at least we can monitor albuterol use, because it must be prescribed by a physician. We have no way of knowing if a patient is taking too much Primatene mist until they are dead.

Under a physician's supervision, with a proper asthma plan and additional chronic maintenance medications for asthma, such as inhaled corticosteroids, bronchodilators can be used safely and effectively. However, over-use of these medications especially in the absence of inhaled corticosteroids is dangerous. This is why I never write an albuterol prescription with any refills. If your asthma is well controlled, one albuterol inhaler should last you a year and you shouldn't need refills. If you are refilling the albuterol more than one time in a year, by the NIH's criteria, your asthma is not under control and you may need to change to a stronger daily medication (for example, switch from Singulair to an inhaled corticosteroid or ICS, or switch from an ICS to an ICS/LABA combination).

For those patients without prescription insurance who relied on the relatively low cost of OTC Primatene mist, be advised the GSK makes a sample size of Ventolin HFA (60 inhalations) that is only $9 out of pocket (regardless of insurance) at most major retail pharmacies. This will of course require a doctor's prescrition, but I believe that is a good thing for the reasons stated above.

Spiriva for Asthma?? Not so fast.

There is a lot of press about a study just published in the New England Journal of Medicine that shows that adding tiotropium (Spiriva) to an inhaled steroid might have benefit in asthmatic patients. This study is creating a lot of buzz due to recent concerns of ICS/LABA safety and might prompt doctors and patients to start switching (some already have before this study came out). However, this would be a HUGE mistake.

The study was a small study of 210 patients that compared the addition of tiotropium (Spiriva) which is a a long-acting anticholinergic inhaler currently only used in the treatment of chronic obstructive pulmonary disease (COPD) to an inhaled corticosteroid (ICS), and compared this to
doubling of the dose of the ICS or adding the long-acting beta agonist (LABA) salmeterol.

The primary endpoint of the study was improvement in morning peak flow, which they found that adding tiotropium increased by 25.8 liters per minute (P<0.001) as compared to doubling the dose of the ICS. There was also improvement in secondary outcomes such as lung function as measured by FEV1, which showed an improvement of 0.10 liters (P = 0.004). In addition, when comparing additng tiotropium or salmeterol to ICS (the study was designed to show tiotropium was no worse), they found tiotropium slighlty better than salmeterol in terms of morning peak flow (6.4 liters per minute (P<0.001)) and not significanlty different in lung function (FEV1 difference of 0.11 liters).

With some safety concerns regarding the use of LABA's, (I have blogged about this before and the bottom line is that if taking with an ICS, there seems to be no problems with LABA's) the New England Journal article might tempt doctors to use tiotropium instead of a LABA in asthmatic patients, if the evidence suggests that the benefit is similar between Spiriva and Salmeterol. However, making this leap would be dangerous for several reasons.


1. Almost all the data supports the use of LABAs. This is an intriguing but small study. Clearly more studies are warranted. However, the question of adding LABA's vs doubling the ICS dose has been extensively well studied. The best source is the unbiased Cohrane Review. Their review included 48 studies (15,155 participants including 1155 children and 14,000 adults). In looking at the morning PEF (the New England Journal article's main end point), the Cochrane group found that adding LABA to an ICS (compared to doubling the ICS dose) showed a 16.30 L/min improvement from baseline. This is similar to what was found in the New England Journal study. In looking at FEV1, the Cochrance group found an improvement of 0.08 (CI 0.03 to 0.13), which is closer to what was found with Spriva and much higher than what was seen in the New England Journal study. In other words, in looking at 48 studies with thousands of patients, ICS + LABA performs a little better than it did in the New England Journal study, although it does not clearly beat the numbers of tiotropium.

2. There is no data on outcomes such as exacerbations. A small bump in peak flow or lung function is meaningless if patients are still getting sick. The main goal of asthma treatment is to prevent exacerbations. The New England Journal study was too small to show this. However, the Cochrane review clearly shows that adding a LABA to and ICS, compared to doubling the dose of the ICS clearly prevents exacerbations. They showed a statistically significantly lower risk of exacerbations requiring systemic corticosteroids in patients treated with LABA and ICS (RR 0.88, 95% CI 0.78 to 0.98, 27 studies, N = 10,578) from 11.45% to 10%, with a number needed to treat of 73.

3. There is no ICS/tiotropium combination inhaler (yet). One of the advantages to ICS/LABA combination inhalers is that both medications come in a single inhaler. This is critical. As mentioned, the LABA safety issues seems to occur when patients take LABA's without an ICS. This makes sense because even though the bronchodilator might make patients feel better, not treating the disease (inflammation) can lead to serious problems down the line. Because of this, the FDA recently recommned that children who take ICS and LABA's together only take them in the same inhaler. The worrry is that if the two inhalers are used separately, patients are at risk of only taking the brochodilator. Because the bronchodilator makes patients feel better, they are more likely to be adherenct to this inhaler than an ICS, which has effects that patients don't immediately notice. This same concern would be true of tiotropium, which is also a bronchodilator. However, ICS/anticholergic combination inhalers should be available soon. Studies will be now needed not only in COPD, but also in asthma to see which regimen produces the best benefit.

Bottom Line: This is an exciting study. By showing tiotropium has potential benefit in asthmatic patients, it may give clinicians and patients an additional tool to treat this disease. The study shows that use of tiotropium in asthma clearly warrants more research. However, doctors and patients should not start taking ICS and tiotropium over ICS/LABA, since the data (especially regarding exacerbations) is just not there.

Boston Doctors Getting Paid to Switch Patients to Generics

Interesting video from WCVB in Boston about doctors getting kick backs from the insurance company to switch patients from branded medications to generic medications. New Rules To Protect Prescription Drug Customers

If people were concerned about undue influence when drug companies used to give physicians pens and other novelties (now currently banned by most companies), they should really be concerned about actually monetary payments. The patient interviewed in the Boston piece stated his doctor wanted to switch him from Lipitor to generic simvastatin (cholesterol lowering medications) but did not mention that he was being payed by his insurance company to do so.

Though this is the first case I have heard of doctors being incentivized to switch patients to generics, it happens in pharmacies all the time. What is horrible is that some pharmacies may switch patients to alternative medications even if that switch costs the patient more money. The example I am familiar with is albuterol inhalers (see FDA Announces End for CFC-Propelled Inhalers).

Switching to generics is itself not a bad things. I have blogged before that, for most medicines, generics are just as good as brand name medicines. For example, if the patient were on Zocor, a switch to the generic simvastatin would probably make a lot of sense, since the medications are basically equivalent and it would likely save the patient some money. However, in some cases, the small differences may actually make a difference. Back in November, I discussed this in more detail (see Generic and Therapeutic Substitutions ).

In this particular case, the therapeutic switch from Lipitor to simvastatin might have been devastating since Lipitor is a much stronger medication. The piece does not say what dose the patient was on, but if the patient required Lipitor 40mg or 80mg, no dose of simvastatin would have given him the cholesterol lowering he needed.

What should you do?
1. If you are on a branded medication, ask your doctor if there is a generic equivalent of the exact same medicine, or one that works just as well.
2. If you are on a branded medicine and asked to switch to a generic by your doctor, find out why he or she wants to switch.
3. If you are on a branded medicine and asked to switch to a generic by your pharmacy, find out why they want you to switch. Is your insurance company asking for the switch? Is the medicine the same (generic substitution) or slightly different (therapeutic substitution)? Regardless, make sure that you check with your doctor before switching any medicine.

FDA Announces End for CFC-Propelled Inhalers

As reported in Med Page Today, the FDA Announces End for CFC-Propelled Inhalers. Of the seven inhalers with deadlines for removal, only three are still being made:

Flunisolide (Aerobid Inhaler System) on June 30, 2011
Albuterol and ipratropium combination (Combivent Inhalation Aerosol) on Dec. 31, 2013
Pirbuterol (Maxair Autohaler) on Dec. 31, 2013

The reason for this is because CFC's are harmful for the environment, and the newer inahlers have to be replaced with a different, more environmentally friendly propellant called hydroflouroalkane or HFA. I have blogged about this previosuly (please see Asthma inhalers and More on Asthma Inhalers ).

According to the FDA, "patients using the inhalers scheduled to be phased out should talk to their health care professional about switching to one of several alternative treatments currently available. Until then, patients should continue using their current inhaler medication."

What you should do:
1. Albuterol If you are taking albuterol, please see my earlier posts. I still have patients that have their very old albuterol canisters, which are probably no longer effective. An important thing to know is that there is no longer any generic albuterol. More importanly, if your physician writes a prescription for albuterol, the pharmacist will likely give you ProAir, which may or may not be what your insurance prefers and/or what is least expensive for you. This is because many of the chain pharmacies are getting a kick back from the makers of ProAir. Make sure your provider writes for the correct inhaler. All things being equal (same co-pay for patients), I recommend Ventolin HFA (because it is the only one with a dose counter) or Xopenex HFA, because of diminished side effects. NEW INFORMATION: GSK, makers of Ventolin HFA sell a $9 inhaler, regardless of your insurance. Though the inhaler has fewer puffs in it, if you are using your inhaler that frequently, then your asthma is not under good control, and you should be on a different controller medication. Ask your doctor for Ventolin HFA 60 (they have to write the 60 part).

2. Maxair- Some patients love this drug, but it's going away. Before January 2014, get another albuterol. See above and previous posts for advice.

3. Aerobid- I didn't even realize they still made this medication. It is no more effective then other similar medications, probably less effective, possibly more side effects, and it tastes nasty. If you are on this medication, switch ASAP to another inhaled steroid. Good alternatives include Flovent, Pulmicort, Asmanex, and Alvesco.

4. Combivent- This will likely affect patients the most, since few patients are on Maxair or Aerobid, and there are far more COPD patients than asthmatics. It is very likely that before January, 2014, the makers of Combivent with come out with a Combivent HFA. However, there are reasons to consider switching now. Please see older posts Good News for COPD , Bad news for COPD: Why this meta-analysis should be believed (and the Avandia one should not) , and UPLIFTing News for COPD

Briefly, a few studies have come out which make me very concerned about using Combivent. One study published in the Annals of Internal Medicine studied a VA population and found that patients taking ipratropium had significantly higher death rate of about 11%. A second study was a meta-analysis published in JAMA that analysed date from 14,783 patients with COPD and found that patients taking either ipratropium or tiotropium (Spiriva) or both had a 58% increase in cardiovascular death, heart attack or stroke when compared to patients taking other meds (Advair, albuterol or placebo). Though combined, these studies might cause safety concerns with the entire class of anti-cholinergic inhalers, the UPLIFT trial, a long-term, large randomized controlled trial (4 years, almost 6000 patients) which unfortunately failed to show that Spiriva could decrease that rate of lung function decline, did show about 10% relatively fewer deaths. Thus, though anti-cholinergic medicines may cause some harm, it appears that this is likely mainly for the short acting ipratropium and not for the long acting tiotropium. I would therefore recommend that COPD patients talk to their doctors about stopping their Combivent now and switch to a different controller medication (Advair, Symbicort, Spiriva) and/or switch to albuterol alone as a rescure medication.