"Was It Something I Ate?" Asthma and Food Allergies

Food allergies are on people’s minds and in the news. Along with other diseases such as allergic asthma, eczema (aka “atopic dermatitis”), and allergic rhinitis and conjunctivitis (aka “hay fever”), food allergies are common (affecting about 7% of children in the United States) and seem to be on the rise. What are food allergies and how can they relate to asthma? Answering these questions is the goal of this first of a three-part blog entry.

Part 1:

Just what are food allergies? Getting the terms straight.

Studies show that a lot more people think they have food allergies than actually do, but that’s not necessarily because people overcall problems. Rather, it has to do with how the term “food allergy” is defined by western medicine as opposed to its common usage.

In medical parlance, when something unpleasant or harmful happens to a person after eating a particular food, it is referred to as an “adverse food reaction” (AFR). AFR is a broad category, and true food allergy is but one subset of the big AFR group. That is, all food allergies are AFRs, but there are real AFRs that are not allergic reactions. In our more relaxed, common way of speaking, however, we often use the words “food allergy” when we are referring to any kind of AFR.

Here’s an analogy that might help. Consider the set of AFRs to be like the set of motor vehicles. This big group of motor vehicles includes cars, trucks, vans, motorcycles, and mopeds. Maybe it even includes construction vehicles like steamrollers or water craft like speed boats. Now imagine a subgroup of motor vehicles, say trucks. Clearly all trucks are motor vehicles (that is, they belong to that larger set). But there are also motor vehicles that are not trucks (for example, mopeds and steamrollers). So the large category of AFRs is like the large category of motor vehicles, and the subset of true food allergies is analogous to the subset of trucks. The problem arises when someone says “I have a truck” when what that person really meant was “I have a motor vehicle,” because in a colloquial way of speaking we are less rigorous with our terms. That’s why a lot of people report having a food allergy – what they are really saying is “I have an adverse food reaction," and only some of them have a true allergy according to the strict definition.

This is where the analogy above breaks down. Most people who have a motor vehicle can instantly tell whether it is a truck or not – just look at it and one can answer the question, “Is this motor vehicle in the truck family?” Most of us carry around some criteria for answering that question – a truck is the sort of motor vehicle that has at least four wheels, a truck bed, one of a few body shapes, etc.  But how does someone know if his or her AFR is in the family of true food allergies? What are the criteria for that? Turns out it’s not so easy (or impossible) to tell if an AFR is a true food allergy without considering the classic symptoms. And while we’re at it, what does food allergy have to do with asthma anyway?

What are the symptoms of a true food allergy?

After that overly long introduction, it’s time to get down to the real stuff. If food allergies are a subgroup of AFR, exactly what qualifies an AFR to be called accurately a true food allergy? How can we decide if a person is really allergic to a food?

True food allergies are reactions caused by part of the immune system responding to the presence of one or more particular foods taken into the body. These reactions typically occur within a few minutes to a few hours of ingestion of the trigger food(s). So right off the bat, if a person complains of a food allergy causing symptoms a week after he (one time) ate some particular food, we can tell him that he may have had an AFR, but he probably does not have a real allergy to that food

Almost all allergic reactions to a food somehow involve the skin or the moist linings of the body such as the mouth (those moist linings are referred to as “mucous membranes,” “mucosal surfaces,” or “mucosae” for short) with symptoms like itching, flushing, hives, or swelling. Since the food allergen causing the reaction is typically eaten, a lot of food allergic patients have nausea, vomiting, cramping abdominal pain, or diarrhea. When more severe, people may become lightheaded or even faint.

But this blog post wouldn’t be complete if it didn’t mention asthma. People, especially those with known asthma, who experience an allergic reaction to a food can rapidly develop shortness of breath, wheezing, cough, and chest tightness – the classic symptoms of asthma. So while respiratory infections, cold air, exercise, and airborne allergens are among the “most likely suspects” in an asthma attack, add food allergens to the list in some people.

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What Exactly Is "Reactive Airways Disease" Anyway?

“I think that she has a component of reactive airways disease,” the doctor said, describing her otherwise healthy 22-year-old patient with a lingering cough and chest tightness after a respiratory tract infection. “That’s why she has this persistent, wheezy-sounding cough. I’m going to prescribe a bronchodilator and some inhaled steroids.”

“Reactive airways disease.” What is that? I think that I know what the doctor means, but it is hard to be sure. She probably means that following a viral respiratory infection, her patient has sensitized, inflamed bronchial tubes, with asthma-like “twitchiness,” that will benefit from anti-asthmatic medications to relax bronchial smooth muscle (bronchodilators) and suppress airway inflammation (inhaled steroids). And maybe she is correct. But I object to the term, “reactive airways disease,” used to describe what is going on in her patient’s bronchial tubes. Here’s why.

Although I agree that the patient has lingering symptoms and probable airway inflammation following her respiratory infection, I wonder does she really have a “disease” that is being diagnosed other than a viral bronchitis? A disease characterized by “reactive” (that is, constricting more easily than usual) airways? Isn’t that asthma? “Reactive airways disease” sounds to me like “Asthma-like,” or “Asthma-light,” or perhaps “Asthma-but-I’m-not-sure.” But medical providers have the tools available that will allow us to determine whether she has asthma or not. Peak flow measurements, spirometry, exhaled nitric oxide concentration, and bronchoprovocation challenge – there are multiple tools at our disposal.

I understand that in children too young to perform pulmonary function testing, in whom transient wheezing (without asthma) is common and asthma can be difficult to diagnose with certainty early on, the term “reactive airways disease” makes sense as a kind of “place holder,” until the presence or absence of asthma becomes clearer. But the patient we are discussing is 22 years old. Does she have asthma or not? I think that we should be as clear as we can about her diagnosis, rather than slip into the vagueness and ambiguity of “reactive airways disease.”

Why send patients home thinking that they have a newly-diagnosed disease to deal with, when what they have is a lingering cough following a viral respiratory infection, maybe associated with transient bronchial hyperresponsiveness, which will improve with time and/or with our medications?

Yes, but what about that wheezy cough, or wheezing when the patient was asked to breathe out forcefully? Doesn’t that point to something more than an ordinary cough following a cold? Maybe, and maybe not. Let’s check her lung function. If it is normal, then the wheezing is probably not due to asthma with its diffuse airway narrowing involving thousands of bronchial tubes but to central or upper airway narrowing as can be seen in healthy individuals on forceful exhalation and cough, when pressures inside the chest tending to compress bronchial tubes are particularly high. On the other hand, if lung function testing demonstrates airflow obstruction, we have made a diagnosis of asthma (not reactive airways disease). As the maxim goes, “not all that wheezes is asthma” … and not all that wheezes is a disease.

Another reason to avoid the expression, “reactive airways disease,” is that it can easily be confused with reactive airways dysfunction syndrome or RADS, an accepted medical term used to describe a form of occupational asthma. Most occupational asthma develops after many weeks and months of exposure to an inciting inhaled irritant or allergen. On occasion, a single, particularly intense or toxic exposure can cause airway injury and hyperreactivity, referred to as reactive airways dysfunction syndrome, in which the sufferer newly develops asthma after the exposure. I’m not sure that reactive airways dysfunction syndrome is ideal terminology either, but it has a clearer definition and has acquired a more precise meaning than reactive airways disease. The term, RADS, will likely stay, whereas in my opinion we can let the expression “reactive airways disease” go when speaking of adults with cough and wheeze.

New Medications for Asthma

It feels as though there has been a paucity of new medications released for the treatment of asthma. The first of the leukotriene modifiers was made available in 1996; and the anti-IgE monoclonal antibody (omalizumab) came on the market in 2003. There is a short list to mention of newly-released medications since that time, and even then we’ll have to borrow some from the therapeutics of COPD.

New inhaled steroids: Some of you may remember the inhaled steroid, flunisolide, marketed as Aerobid. For some people, it had an unpleasant taste, leading to development of a menthol-flavored version, Aerobid-M. Both brands disappeared with the banning of sale of metered-dose inhalers with chlorofluorocarbon (CFC) propellants, but flunisolide has recently re-appeared in a metered-dose inhaler formulation with hydrofluoroalkane (HFA) propellant, called Aerospan. Unlike other inhaled steroids currently on the market, it is available in only one dosage: 80 mcg/puff. The dose is notably less than its predecessor, Aerobid, which was 250 mcg/puff. The unique feature of the new Aerospan inhaler is a built-in, small-volume spacer, reminiscent of the old triamcinolone inhaler with built-in spacer, Azmacort, that was very widely popular in the 1980s and 1990s (before it too succumbed to the ban on CFCs). Aerospan is approved for children age 6 years and older.

A second newly-released inhaled steroid is fluticasone furoate (Arnuity). A variant of the widely used fluticasone propionate (Flovent), it has been approved for once-daily dosing. The only other inhaled steroid approved by the FDA for use once daily is mometasone (Asmanex), although in truth many patients with mild asthma seem to maintain adequate asthma control when taking their inhaled steroid (regardless of which agent) once a day. Fluticasone furoate is available at two doses (100 and 200 mcg/puff), thereby providing a relatively low daily dose. It has been made available in the novel dry-powder device called Ellipta, which seems exceedingly easy to use. The device is fully prepared when the cover is rotated 90 degrees to expose the mouthpiece. The medication is then inhaled with one deep breath … once a day … and the cover rotated back to close the device. There is a built-in dose counter on the Ellipta which displays the number of remaining puffs with large, easily viewed numbers. This medication has been approved for use in children as young as 12 years of age.

Coming soon? And that’s it for new, approved asthma medications. But let me mention in addition two medications currently approved only for the treatment of chronic bronchitis and emphysema (COPD) that may find their way into asthma care in the near future. One is the anticholinergic bronchodilator, tiotropium (Spiriva). We have previously written in this blog about the observation that this once-daily, long-acting bronchodilator can be used in place of or in addition to the long-acting beta-agonist bronchodilators, salmeterol and formoterol, as add-on therapy to an inhaled steroid in patients with difficult-to-control asthma or among those intolerant of the long-acting beta-agonists. Although not an FDA-approved indication for tiotropium, its use in asthma together with an inhaled steroid represents an alternative to the inhaled steroid/long-acting beta-agonist combinations that are Advair, Dulera, and Symbicort. What’s new here is that tiotropium has recently been made available as a soft-mist inhaler rather than the single-dose, dry-powder inhaler using individual capsules of medication loaded into a device (Handihaler) with each use. The soft-mist inhaler (called “Respimat”) has been used to deliver the combination medication, albuterol plus ipratropium (Combivent), and is now available as an alternative to the dry-powder device for delivery of tiotropium. Two inhalations from the soft-mist inhaler are equivalent to one capsule of the dry-powder preparation. Its major advantage is that each canister of the soft-mist inhaler contains 60 doses or a one-month’s supply. Each day’s dose does not need to be prepared separately. Tiotropium’s safety has not been tested or documented in children.

Finally, the once-daily inhaled corticosteroid mentioned above, fluticasone furoate, has been combined with an ultra-long acting inhaled beta-agonist bronchodilator, vilanterol, into a combination called Breo. These medications are delivered from the same multi-dose, dry-powder inhaler used with fluticasone furoate alone, the Ellipta. The once-daily inhaled steroid/long-acting beta agonist combination (Breo) has been approved for use in COPD; its package insert specifically indicates “not for use in asthma.” However, clinical trials in asthma sponsored by its manufacturer (GlaxoSmithKline) have documented the safety and efficacy of Breo in asthma; and an FDA Advisory Panel has recently voted in favor of giving approval to Breo for treatment of asthma.

If approved, Breo will be, in a sense, a once-daily Advair; that is, an inhaled steroid/long-acting beta-agonist combination delivered from a multi-dose, dry-powder inhaler. Although dosing is still to be determined, studies have explored two steroid concentrations: 100 and 200 mcg of fluticasone furoate combined with 25 mcg of vilanterol. Children as young as 12 years of age have been enrolled in these clinical trials.

And stay tuned: clinical trials are underway using a combination once-daily anticholinergic bronchodilator (umeclidium) combined with fluticasone furoate in a multi-dose, dry-powder inhaler in the treatment of asthma. It is a reasonable assumption that persons with asthma will be more faithful to daily medication use if their medications need to be taken only once a day ... as long as they are effective and have few side effects.

Suddenly Unable to Breathe

A young man came to see me the other day complaining of several episodes of frightening shortness of breath. The first episode developed quickly one day when he was leaving work. He had been tired that week, perhaps with early symptoms of a respiratory tract infection or perhaps his allergies were acting up, but his distress seemed to come on “out of the blue.” Quite abruptly, he recalled, he couldn’t breathe. His symptoms improved relatively quickly, such that by the time he arrived home 30 minutes later he felt all better, although frightened by such a severe attack.

He experienced several similar events over the next few weeks, many waking him from his sleep. He had no prior history of asthma, although he had a history of mild seasonal rhinitis. He experienced occasional post-nasal drip and had no symptoms of heartburn to suggest gastroesophageal reflux. He had never been told of asthma as a child, and he was a lifelong non-smoker.

When questioned more about his difficulty breathing, he was quite clear: he simply could not get air in or out of his chest. It was not that it was hard to empty the air from his chest, he said, it was that no air would move at all. He was given an albuterol inhaler to try, but found it difficult to use and in truth had not tried it.

He reported only minimal cough, no sputum production. He had not experienced wheezing, but recalled a respiratory sound that he made as his episodes gradually resolved. His wife thought that she too had heard a breathing noise, particularly when he tried to breathe in. They have two cats at home but noted no increased likelihood of symptoms when around the cats. In the absence of these attacks, he felt well and was able to work out at the gym without limitation due to his breathing. His only medications were vitamin D and glucosamine chondroitin.

His chest examination was normal. Chest X-ray was normal. Breathing tests (spirometry) performed at a time when he felt well was likewise normal. And the question was: is this asthma?

Asthma causes symptoms that come and go. Between attacks one can feel entirely well with a normal chest exam and normal lung function. However, the history that this young man offered was atypical in several ways, including no prior history of asthma; sudden severe attacks that came on without warning and resolved within a few minutes without treatment; and his sense that during these spells it was not hard to breathe, but impossible to breathe at all – no air movement in or out at all. As the episode abated, there came an inspiratory sound; and when asked if he could localize the site of his distress, he offered that he thought his problem was in his throat more than in his chest.

The diagnosis? Not asthma but laryngospasm – an alternative and more plausible explanation for these sudden attacks of difficulty breathing. Imagine that some irritant triggers the vocal cords to suddenly come together and tightly obstruct the upper airway. One cannot breathe (or talk), and it feels as though one were about to suffocate to death. One tries to inhale or exhale, but no air can pass the closed glottis. After what seems like an eternity but is probably well less than one minute, the laryngeal spasm begins to abate. As the vocal cords begin slowly to move apart, one can start to get air passed, with an inspiratory sound that we recognize as stridor. At first air enters the lungs with increased resistance through the narrowed upper airway, but over several seconds, as the laryngeal muscles further relax and the vocal cords abduct fully, normal breathing is restored. The entire event is over in a minute or two, and no medication is needed (or likely to help). An inhaled bronchodilator might be more irritating to the larynx and should probably be avoided.

What causes some people to develop laryngospasm is not known. Our young man had a normal ENT examination with direct laryngoscopy to exclude a structural abnormality of the glottis. His laryngeal sensitivity developed without prior trauma or other explanation. Potential triggers that may set off spasm of the sensitized larynx include mucus draining from the posterior pharynx, acid refluxed from below, cough with secretions expectorated at high velocity, or oro-pharyngeal aspiration.

Preventing provokers of laryngospasm, such as laryngopharyngeal reflux, is an important treatment, especially in persons with frequent night-time episodes. Other management strategies that have been described include “rescue breathing” techniques taught by speech-language therapists; application of forward and upward pressure behind the earlobes and in front of the mastoid processes in what has been described as the “laryngospasm notch”; and, rarely, botox injections into the larynx.

In most instances, coming to understand the mechanism of the event is key to dealing with it: one needs to try to stay calm, attempt small breaths in through the nose, and perhaps visualize relaxation and separation of the vocal cords. Knowing that the spasm of the larynx will pass in a matter of seconds and that there will be no long-term harmful effect are the reassurances that we have to offer. Distinguishing these episodes from asthma attacks is also crucially important. Treatment with bronchodilators and corticosteroids will not bring relief or prevent episodes of laryngospasm. It only confuses the issue, obscures the diagnosis, and likely frustrates the sufferer.

"... and now I'm hoarse too"

Persons with asthma can have plenty of symptoms that they have to deal with, whether it’s shortness of breath, chest tightness, a noisy chest, or troublesome cough. At the same time nasal allergies can cause a stuffy or drippy nose, sneezing, or frequent throat clearing from post-nasal drip. And then we frequently hear about a hoarse voice. It often comes and goes and can be a considerable frustration, especially for those who do a lot of speaking in their work. The voice quality changes; people notice that your voice doesn’t sound the same, and sometimes it seems like more work to generate a normally loud voice. What is causing this problem on top of everything else?

There are a number of potential causes, just as in persons without asthma, such as trauma from repetitive coughing, gastroesophageal reflux disease (GERD) causing stomach acid to splash onto the vocal cords, or polyps forming along the vocal cords. But an important consideration in persons with asthma is hoarseness as a side effect from use of the medications, inhaled steroids. Examples include the inhaled steroids taken alone (Flovent, Pulmicort, Qvar, Asmanex, Alvesco, and Aerospan) as well as the inhaled steroids taken in combination with long-acting bronchodilator medicines (Advair, Symbicort, and Dulera).

You probably know that it is a good idea to rinse your mouth after using these inhalers in order to prevent a throat infection referred to as “thrush” or oral candidiasis, caused by the yeast, Candida. You cannot, however, rinse down to the level of your vocal cords, which sit behind your “Adam’s apple” in the middle of your neck. Some of the steroid medication that you are inhaling will settle on the vocal cords on its way down onto your bronchial tubes, with the possibility of causing irritation and voice weakness. This is an undesirable effect of the steroid medication – an “inhaled steroid-induced laryngitis.” It is more common when the medication is delivered by metered-dose inhaler rather than dry-powder inhaler, and it is probably more common when the dose of medication is higher. It occurs with all of the inhaled steroids, but not commonly with inhaled bronchodilators alone (such as albuterol), so it seems to be an effect of the medication, not the propellant or powder being inhaled.

No one knows exactly in what way the inhaled steroids affect the vocal cords to cause hoarseness. Some have thought that they cause a weakness of the muscles involved in bringing the cords together during speech; others have thought that there is irritation to the surface membrane that covers the cords. Occasionally, one can find candida infection of the vocal cords. The inhaled steroids do not cause throat cancer or permanent injury to the vocal cords.

Inhaled steroids are the cornerstone of long-term asthma treatment. They reduce symptoms, make the bronchial tubes less hypersensitive to the triggers of asthma, and help to prevent asthma attacks. Their increasingly widespread use is probably the reason for the reduction in asthma hospitalizations and deaths observed in the United States over the last 2 decades. Hoarseness is a frustrating side effect that affects some people who use these highly-effective medicines, even when they are doing everything right in their use.

What can be done? If you can safely omit use of your inhaled steroid for a period of time, your voice quality will return to normal. Sometimes it takes only a few days, sometimes a few weeks. You can try adding a spacer to your metered-dose inhaler or switching from a metered-dose inhaler to a dry-powder inhaler for delivery of your inhaled steroid. There is no good evidence that one inhaled steroid has fewer effects on the voice than any other, although there is some theoretic reasoning to suggest that ciclesonide (Alvesco) might cause less hoarseness. If your hoarseness is severe and persistent, it would be good to have a direct examination of the vocal cords performed by an otolaryngologist (ENT doctor), to exclude alternative reasons for your hoarseness. Meanwhile, we continue to seek better medicines to treat asthma -- effective and free of side effects.

E-cigarettes: smoking cessation aid or new addictive public health hazard?

“Vaping” is taking off in the U.S. and elsewhere around the world. With the encouragement of big tobacco companies, more and more people are trying electronic cigarettes as an alternative to tobacco-filled cigarettes. Should we be encouraged by the availability of a safe alternative to conventional cigarettes or dismayed by a new, addictive nicotine-containing product unleashed to the general public, including children, without regulatory oversight?

Why do we offer our opinion about e-cigarettes in a blog about asthma? We do so because: 1) many people with asthma smoke cigarettes, probably similar in frequency to the 19-20% of the general population who continue to smoke in the United States; and 2) we hate cigarette smoking! Our medical lives are filled to overflowing with smoking-related medical disasters, whether the slow suffocation of advanced emphysema or the horrible, inexorable death from incurable lung cancer (the cause of more cancer deaths in the United States than the next 3 most common cancer killers – colon, breast, and pancreas -- combined). Persons with asthma who smoke cigarettes put themselves in “double jeopardy,” with airway disease due to asthma combined with airway disease and emphysema due to cigarette smoking (chronic obstructive pulmonary disease or “COPD”), while at the same time interfering with the beneficial effects of some of the asthma medications (the inhaled steroids).

At first blush, then, we are inclined to embrace the idea of an alternative to cigarettes without the tar and other products of combustion that predispose to the development of cancer and other diseases, like heart attacks and strokes. As physicians, we are constantly seeking aids that can help persons who are addicted to cigarettes stop smoking. We have nicotine-containing patches, gum, nasal spray, and lozenges that we can recommend, even a small, nicotine-containing cartridge that can be placed in a plastic cigarette holder to inhale nicotine to the lungs (Nicotrol®). What’s wrong with a novel nicotine delivery system, the e-cigarette, which mimics smoking more closely, with a warm mist to inhale and a visible puff of smoke to enjoy “guilt-free?”

Well, here’s our list of what’s wrong with the e-cigarette:

• We don’t know exactly what is in the e-cigarette vapor. It contains nicotine, propylene glycol, often flavoring, and perhaps other chemicals. The amount of nicotine (and other chemicals) in each cartridge is not closely regulated. The long-term effects of inhaling this vapor into the lungs are unknown. Wouldn’t you like to know this information before promoting “vaping” as a safe alternative to cigarette smoking?

• One could imagine that widespread availability of e-cigarettes, aggressively marketed to children and young adults, could lead to an increase in persons addicted to nicotine and going on to take up cigarette smoking, rather than a decrease. We have witnessed over the last few decades a national change in attitude toward cigarette smoking, restricting smoking at work, in public places, in and around schools, restaurants, bars, airplanes, some hotels, etc. It is no longer the norm. What would the implication be of unrestricted use of e-cigarettes … at the workspace or restaurant table next to yours? What’s the risk of second-hand e-cigarette vapor exposure, anyway? We don’t know.

• Nicotine is highly addictive, even without all the other poisons in tobacco smoke. Do we as a nation need to offer inhaled nicotine as an unregulated drug, including to children, pregnant women, nursing mothers, persons with heart disease, and the elderly? Several countries around the world have banned the sale of e-cigarettes. Britain plans to regulate it as a medicine.

What should the U.S. Food and Drug Administration do, on our behalf?

We would favor making e-cigarettes available like the Nicotrol® inhalation system, with a prescription, to be used for the medical indication of smoking cessation. The FDA could closely monitor and control the contents of e-cigarettes and insist that the chemical components be clearly displayed on the product, like ingredients in a skin cream. The agency could also insist that medical studies be performed to ensure the short-term and long-term safety of the medication, or to develop clear labeling warnings about the potential health risks … as for other drugs. The manufacture and sale of e-cigarettes has already become a multi-billion dollar industry; there should be plenty of money to spare to do safety testing on the product, along with assessment of its effectiveness as a smoking-cessation aid.

The Forum of International Respiratory Societies, a consortium of professional respiratory societies and experts in respiratory medicine from around the world, recently released a position statement regarding electronic cigarettes. They recommended a ban on the sales of e-cigarettes; or if not a ban, regulation as medicines; or if not regulated as medicines, regulation as tobacco products. The publication is in press; an abstract is available at the following link: http://www.atsjournals.org/doi/abs/10.1164/rccm.201407-1198PP

Should We Bring Back Primatene Mist?

Imagine that you have been chosen to serve on a Food and Drug Administration (FDA) Advisory Panel that is being asked to review the application to approve a re-formulated Primatene Mist® for sale over-the-counter. Primatene Mist contains the bronchodilator, epinephrine. For decades it was available without a prescription, with many millions of inhalers sold. It was taken off the market at the end of 2011 because of the general ban on medications using the environmentally-harmful propellant, chlorofluorocarbons (CFCs). Primatene Mist has been redesigned now with the ozone-safe propellant, hyrdrofluoroalkanes (HFAs), and its manufacturer (Armstrong Pharmaceuticals) seeks to have it put back onto the shelves of pharmacies, markets, and convenience stores. How would you vote: “Yay” or “Nay”?

Let’s try to lay out the arguments, for and against approval. We recognize that there are many strongly held opinions on the topic, as a quick read of the “BringBackPrimateneMist” facebook page would suggest.

In favor of approval:
• Many people with asthma do not have a primary care provider to write for them prescription bronchodilators. They too need access to medication that can help their breathing, especially in an asthma crisis. This disparity of access to medication is especially pertinent to asthma, where the poor and minorities bear the greatest burden of the disease. Even some people with health insurance may find an over-the counter medication less expensive, and it can be purchased in a jam, when you discover that you have left your prescription bronchodilator at home.
• Epinephrine by metered-dose inhaler has been used by millions of people over more than 4 decades, suggesting its safety.
• Epinephrine is an effective bronchodilator that begins to work quickly (onset of effect within 1-2 minutes), though with a relatively short duration of effect (1-3 hours).

Against approval:
• Compared to newer (prescription) bronchodilator medications like albuterol (ProAir, Proventil, or Ventolin), epinephrine is more likely to cause heart racing and tremor.
• Selling a bronchodilator over-the-counter means that it can be obtained without medical guidance as to when, how often, and how much to use. Package labeling may carry this information, but more often than not it goes unread.
• An OTC medicine is available for purchase by children without medical or parental guidance.

Our take:
Primatene Mist sold over-the-counter perhaps made sense in an earlier era when our conception of asthma was a disease of bronchial muscle constriction. Take a bronchodilator medication that relaxes tightened bronchial muscles, open your narrowed airways, and all we be restored to normal. We now know better. Shortness of breath, cough, and wheezing are often due in large measure to allergic (or non-allergic) inflammation of the airways, with swelling of the airway walls and excess mucus production filling the bronchial tubes. Relying on a bronchial muscle relaxer to relieve symptoms leaves much of the cause of the problem untreated. By offering ready access to a medicine that treats only one aspect of asthmatic airway narrowing – temporarily – one invites insufficient treatment, delayed treatment, and the risk of more, not fewer, severe and dangerous asthmatic attacks. It is a step back in time for asthma treatment, not a well-reasoned advance forward. Why would one make an older, less effective bronchodilator available over-the-counter and restrict newer, safer, more effective bronchodilators to prescription only? Perhaps the way forward …in an attempt to make low-cost bronchodilators quickly available to persons who need them … is to make albuterol available over-the-counter in limited doses (for instance, in an inhaler with no more than 20 inhalations per device). The inhaler would provide enough doses to “buy time” while one seeks medical help, not so many that one relies solely on the bronchodilator medication and delays other crucial, potentially life-saving therapies. Of course, one could buy more than one such inhaler at a time, but the message would be clear: the bronchodilator inhaler is for short-term, quick-fix use only.

We recognize that this topic is controversial. Looking for allies to support our point of view, we have found the American Thoracic Society, the American College of Allergy, Asthma, and Immunology, and the American Association of Respiratory Care. We would note that the FDA Nonprescription Drugs Advisory Committee and the Pulmonary-Allergy Drugs Advisory Committee did meet to discuss Primatene Mist-HFA and voted in February against approval. The FDA has yet to make its final decision.

Our New Year's Asthma Wish List

Living with asthma can be full of frustrations and sometimes worse, imposing limitations and causing frightening flare-ups or “attacks.” We would like the asthma to just “go away,” so that at the top of our 2014 Wish List for asthma is finding a cure. And some days it feels as though we are getting closer – if not to a cure, at least to primary prevention. Interesting research into the low rates of asthma among children reared on small farms, brought up in close contact with farm animals and the detritus in their stalls, has led to speculation that introducing harmless germs into the environment of young children … the right germs in the right combination, at the right time, by the right route (ingested or inhaled?), in the right amount, and for the right duration … might lessen the risk of developing asthma. But short of eliminating asthma all together, here is our wish list – the “short list” -- for improvements in asthma care that we think are, or should be, within our grasp.

1. Low-cost, generic asthma medications. Ten years ago a generic albuterol inhaler was available without insurance coverage for less than $20. With the banning of inhaled medications using chlorofluorocarbon (CFC) propellants beginning in 2009, generic albuterol disappeared from sale, replaced by brand-name versions of albuterol with the hydrofluoroalkane (HFA) propellant, such as ProAir, Proventil, and Ventolin, all considerably more expensive. And despite their availability now for several decades, inhaled corticosteroids by metered-dose inhaler or dry-powder inhaler have never had a generic version available. It is true that generic albuterol and the inhaled steroid, budesonide, are available for nebulization, but it is not practical to ask all persons with asthma to administer their medications by nebulizer over 5-10 minutes for each dose, let alone carry a nebulizer with them at all times for emergency use. The Food and Drug Administration (FDA) should ease whatever restrictive regulations prevent release of generic albuterol-HFA and at least one generic inhaled corticosteroid, such as beclomethasone (first released in the United States in the early 1970s) or fluticasone (first released in the US more than 30 years ago).

2. Reduced medication side effects. On the bright side, most persons with asthma can achieve good asthma control (rare symptoms and freedom from asthma exacerbations) with currently available medications taken once or twice daily. Unfortunately, though generally well tolerated, these medications are not free of side effects. In particular, we are struck by how often our patients taking an inhaled medication that contains a corticosteroid complain of hoarse voice. Other side effects from the inhaled steroids include the risk of a yeast infection in the mouth (oral candidiasis or “thrush”) and, after many years of use at high doses, a slightly increased risk of cataracts, glaucoma, and loss of bone mass (osteoporosis). In growing children, slightly slowed vertical growth (ultimate height reduced on average by approximately 1/4-1/2 inch) is a concern. Although we can’t expect our medications to be entirely free of all undesirable effects, these are annoying side effects that sometimes limit use and are a worthy target for drug development or drug modification.

3. Identical health outcomes for people of color with asthma. More than twenty years ago epidemiologic studies identified the unequal distribution of asthma morbidity and mortality in the US. The rates of hospitalization and death due to asthma among African-Americans and Hispanics were 3-4 times greater than among whites. Now, after three releases of Guidelines for the Diagnosis and Management of Asthma by the National Heart, Lung, and Blood Institute of the National Institutes of Health to care providers throughout the US, the overall rates of hospitalization and death from asthma are decreasing, but racial and ethnic inequalities remain unchanged. In the US the color of one’s skin is a risk factor for dying from a severe asthma attack. Exactly why this injustice persists is uncertain, but it is likely that increased rates of poverty among persons of color play a major role. Addressing poverty and its link to poor asthma care is not an easy assignment, but it is not insurmountable. The work of Dr. Paul Farmer and Partners in Health in Haiti and elsewhere around the world should inspire our efforts in asthma care here in the US.

4. Novel therapies for severe, refractory asthma. Although most persons with asthma can achieve good asthma control with currently available medications, some cannot. It is estimated that as many as 20-25% of persons with asthma continue with frequent symptoms and multiple asthmatic attacks despite faithful use of strong, best-that-we-have asthma medications. Even if the true percentage were less, say 10%, that would mean that nearly two million Americans are in need of newer, more effective therapy for their asthma. Research is progressing in the development of novel medications for this subgroup of persons with “refractory” asthma. Designer molecules (called monoclonal antibodies) are being developed that will block the recruitment of allergy cells (eosinophils) to the bronchial tubes and inhibit powerful inflammation-stimulating molecules. Examples include monoclonal antibodies against interleukin 5 (mepolizumab and reslizumab), interleukin 13 (lebrikizumab), and the shared molecular receptor for interleukin-4 and 13 (dupilumab). Although the promise of these new biologic therapies is great, they are destined to be hugely expensive and require administration by injection or intravenous infusion. The search for alternative, simpler small molecular inhibitors of key biologic processes in asthma continues.

5. Preventing dangerous asthma attacks: “An app for that.” Despite our progress in treating asthma -- by targeting the underlying inflammation of the bronchial tubes as well as preventing spasm of the bronchial muscles that can tighten around our airways -- dangerous asthma attacks continue to occur. Nearly two million times a year persons with asthma rush to the emergency department of a hospital for treatment of asthma attacks. Sometimes these attacks develop gradually, as cough and chest tightness evolve into greater and greater breathlessness. Sometimes they catch us by surprise, lacking the usual warning signs; suddenly we are in a crisis, unable to breathe and desperately seeking quick relief. Even then, some of these sudden attacks may have had warning signals, if we had been able to perceive them. In general, narrowing of the breathing tubes comes on gradually, over hours to days, as swelling of the tubes develops, mucus forms, and the bronchial muscles tighten their grip. In this age of electronic self-monitoring, we need a smartphone app for tracking asthma and preventing early asthma attacks from progressing to such severity that they become life-threatening. There exist apps with fitness wristbands that track our activity level, calories burned, and even how much and how well we slept. Our New Year’s asthma wish list includes the asthma app that will sound the alarm to tell us when to take action because our asthma is getting out of control.

With our best wishes for a healthy and wheeze-free New Year!

"Can You Show Me How You Use Your Inhaler?"

This year a new type of delivery device for inhaled medications has become available. It is used to deliver the bronchodilators albuterol and ipratropium in combination (Combivent) and is called a “soft-mist” inhaler. With activation, a slow-moving mist of medication – somewhat like the aerosol from a nebulizer – is released for approximately 1½ seconds. A full dose of medication is contained within the mist, which is to be inhaled from the mouthpiece of the device. The soft mist inhaler joins a variety of other devices, including metered-dose inhalers, dry-powder inhalers, and hand-held nebulizers, used to deliver medications by inhalation. What strikes us as remarkable – and the subject of this blog -- is the daunting challenge faced by persons with asthma (and other lung diseases) as they try to master use of these very different inhaler devices. Some of the devices release a plume of medication traveling at high speed; others come in the form of a powder that is turned into an aerosol only by the force of a breath in. Some are best combined with a hollow chamber (“spacer”) that will hold the medicine in a confined space for a second or two prior to breathing it in; others cannot be combined with a spacer. Some medications come in more than one form – metered-dose inhaler and liquid for nebulizer; metered-dose inhaler and dry-powder inhaler – although most do not.

What we wish to share in this blog is the way that we teach inhaler use. As part of the “package insert,” each device comes with instructions that describe the steps involved in preparing and then inhaling the specific medication, and many companies provide additional printed hand-outs, often in multiple languages. In addition, video instructions are often available on-line. Nonetheless, in our opinion, there is no substitute for live demonstration in the office. It takes no more than a minute, it can be repeated as often as necessary, reading skills and internet access are not required, and there is no charge or adverse side-effect! If available, a placebo demonstration device is very useful; otherwise, role play also works well.

Here’s what we say for metered-dose inhalers: shake the medicine one or two times; with the device held upright (mouthpiece at the bottom), put the mouthpiece between lips and teeth and seal your lips around it. To release the medicine, depress and then release the canister in its plastic holder held between thumb and index finger; and then immediately take a slow, deep breath in. Slow and deep allow the medication to enter deep into the lungs (instead of impacting on the back of the throat) and to deposit onto hundreds of bronchial tubes, large and small. A slow, steady breath over 4-5 seconds should do the trick. Then hold your breath for a few seconds before exhaling, to prevent losing much of the medication in the exhaled air.

In our experience, the “slow and deep breath in and then hold your breath a bit” are the parts most often omitted. We all find ourselves too busy, in too much of a hurry, too focused on other things to concentrate on the act of properly using our inhalers. And yet it makes a difference, often a big difference. The difference between poorly-controlled asthma and well-controlled asthma can at times be a matter of properly inhaling one’s current medications, rather than escalating the dose of medicine or changing from one medicine to another.

A spacer can be used with metered-dose inhalers and helps to relieve the “stress” of getting exactly the right timing between squirting the medication from the device and immediately beginning to breathe in. By releasing the medication into the confined volume of the spacer, one can then, stepwise, breathe in only after the medication is where you want it, waiting to be pulled from the chamber into the lungs. Still, the subsequent steps are key, as before: slow and deep breath in and hold your breath for perhaps 5 seconds. Besides helping with the timing of hand-breath coordination, the spacer reduces the amount of medication that would otherwise settle on your tongue and throat. For steroid medications like flucticasone (Flovent), this means less steroid available to be swallowed and absorbed from your stomach into the rest of your body. If you are well-skilled in using your quick-relief bronchodilator inhaler such as albuterol (Proair, Proventil, or Ventolin), then you need not tack on a spacer. If you have trouble coordinating your inhaler – and, in the case of steroids, to reduce the amount of steroids settling on your mouth and throat -- the spacer is a useful addition.

No plume of medication is released from dry-powder inhalers. With the force of one’s breath in, one turns the collection of powder in the inhaler into an aerosol that can be breathed deep into the lungs. Each device is prepared for the next dose of medication in a slightly different way, but when the medication is ready to be released, the process is the same: seal your lips around the mouthpiece, take in a strong breath to pull the medication out of the device, continue a long and deep breath in to distribute the medication widely throughout the lungs, and then hold your breath for a few seconds before exhaling. Again, the long and deep and then hold your breath steps are the ones that we want to emphasize. A short, quick gasp puts medicine primarily on your uvula and windpipe without getting it far out onto the bronchial tubes where it is needed. Spacers cannot be used with dry-powder inhalers (including those that deliver steroid medication).

We recognize that many other things get in the way of our taking medications regularly for a chronic condition. An article in The New York Times recently highlighted the issue of exorbitant medication costs. And there are many other obstacles to adherence to the medical provider’s prescription: dislike of medication side-effects; concerns about long-term medication safety; fears of medication dependence or loss of potency over time; confusion when choosing among different inhalers; and forgetfulness, to name a few. It is estimated that daily use of an inhaled steroid for asthma among those prescribed a steroid inhaler for daily use is 40% or less. Still, we believe that one of the reasons for not taking your preventive inhaler and getting the most out of it should not be: “my doctor never showed how I was supposed to use it.”

Intermittent Use of Inhaled Steroids for Mild Asthma

For decades now, guidelines for asthma care have recommended that persons with persistent asthma should take daily anti-inflammatory medication, preferably an inhaled steroid, to lessen their symptoms of asthma and reduce the frequency of flare-ups of their disease (asthma “attacks”).  At the same time, it has been suggested that persons who have very mild disease and few symptoms (“intermittent asthma”) can use their quick-relief bronchodilator as needed and need no other medication for their asthma.  Inhaled steroids have not been recommended for persons with mild and intermittent asthma because: 1) infrequent symptoms do not seem to warrant daily medication, and 2) evidence indicates that long-term use of inhaled steroids does not improve lung function over time or affect long-term outcomes in asthma.

Panels of experts write the asthma guidelines based on their experience and available scientific information.  (The guidelines are not divinely inspired or carved in stone tablets!)  Asked to define “persistent asthma,” the experts reached the following consensus: anyone who has two days or more of asthma symptoms each week or wakes up two or more times with asthma symptoms each month or has lung function that is below normal or has had two or more attacks of asthma (requiring oral steroids) in the past year.  Taken as a whole, patients with persistent asthma who are treated with regular (daily) inhaled steroids have fewer symptoms of their asthma, less need for their “rescue” bronchodilator, better lung function, fewer asthma attacks, and an overall improved sense of well-being. 

But a fair question – and one that has now been addressed by recent clinical research – is exactly where one should draw the line between “intermittent” and “persistent” asthma.  Did the experts get it right, or are there patients with persistent (as defined above) but mild asthma who do not in fact need to take an anti-inflammatory medication daily for relief of symptoms and prevention of asthmatic attacks?  If you have mild persistent asthma and your symptoms are sufficiently few (more than two days out of the week but less than every day), prior asthma attacks have been sufficiently rare, and breathing tests are for the most part normal, might you take inhaled steroids only during periods when your asthma is troublesome but stop them during times when your asthma is no longer bothering you?  It is very likely that many patients with asthma have been following this practice for years – because daily medication use can be onerous – but is it safe and advisable?

Two studies – one in adults [Boushey et al., New England Journal of Medicine 2005; 352:1519] and one in young children [Zeiger et al., New England Journal of Medicine 2011; 365:1990]  – have indicated that the strategy of using inhaled steroids intermittently, only during periods of increased symptoms, is indeed safe for persons with mild persistent asthma.  These studies found that among persons with mild persistent asthma there was no difference in the frequency of asthma attacks, including severe or dangerous attacks, and very little overall difference in sense of well-being whether they used their inhaled steroids every day vs. used them only when symptoms became troublesome … as long as everyone had a plan regarding how to deal with an asthma attack. 

Let’s be specific.  Based on these recent studies, if your asthma has been mild, your medical provider might prescribe for you an albuterol (ProAir, Proventil, or Ventolin) or levalbuterol (Xopenex) inhaler to use whenever you need it.  If you find yourself using your quick-relief bronchodilator a lot, or if you feel congested at the start of a “cold,” or if you are visiting your in-laws who own a cat to which you are allergic, you would begin your steroid inhaler, such as fluticasone (Flovent), budesonide (Pulmicort), beclomethasone (Qvar), mometasone (Asmanex), or ciclesonide (Alvesco).  You would probably take at least four inhalations morning and night every day for approximately ten days, and then when you felt better, didn’t need your rescue bronchodilator so often, had gotten over the cold, or were no longer exposed to the pet cat, stop your steroid inhaler.  And you would be prepared with the knowledge that if your symptoms worsened despite taking the inhaled steroid, you would need to begin oral steroids (e.g., prednisone or Medrol) and be in contact with your healthcare provider.

Two important caveats before one puts this approach into practice.  First, it is not intended for persons with more severe forms of asthma.  Our emergency departments routinely treat persons with asthma who had been doing well until they stopped taking their preventive asthma medication (their inhaled steroids), thinking that they no longer needed them, and then developed severe asthma symptoms.  In persons with moderate and severe persistent asthma, evidence is unequivocal that reducing the dose and then stopping inhaled steroids is associated with more asthma attacks and worse asthma control.  Second, intermittent use of inhaled steroids does not mean “as needed” or “p.r.n.”  For this new strategy to work, the inhaled steroids need to be taken not here and there trying to relieve symptoms but every day, usually twice a day, for a period of 1-2 weeks or more.  Intermittent use of inhaled steroids refers to regular, daily administration, but for a limited period of time rather than year-round indefinitely.

In the future, another group of national and international asthma experts will write an updated set of asthma guidelines and render its opinion regarding this approach to asthma care.  In the meantime, our opinion is that this is a safe and reasonable way to treat mild asthma.  It is not appropriate for persons whose asthma is more severe, and its implementation requires careful explanation and reinforcement such that everyone is clear as to when to begin the inhaled steroids, how to use them and for how long, and what to do if asthma fails to improve as expected.

A Steroid "Burst"

We recently received an e-mail from overseas commenting that a steroid “burst” does not translate well.  It sounds too violent, like an explosion.  Now that we think about it, a steroid “burst” does sound like something one might see at a Fourth of July fireworks display!  But you know what we are referring to: that time-limited course of prednisone or methylprednisolone (Medrol) taken by mouth to quiet a flare of out-of-control asthma.  Most persons with asthma have a love-hate relationship with oral steroids.  Love: the medicine helps you breathe normally again, “better than ever,” at a time when your other medications seemed no longer to work.  Hate: it often has unpleasant side-effects, such as stomach discomfort, moodiness, agitation, sleeplessness, and, of course, the “hungry horrors.”

What may have struck you … as it does us … is that no one seems to know the exactly “right” way to prescribe a steroid “burst.”  Sometimes you are given 40 mg of prednisone to start, sometimes 60 mg.  If you went to the Emergency Department to receive your first dose, it may have been given intravenously at twice the amount, as methylprednisolone (Solu-Medrol) 125 mg.  After the first dose you may have been given 5 days of treatment, 14 days, or longer.  And the dose may have been reduced from its initial large amount to zero in various ways – by 10 mg/day every day or every two days, by 20 mg every 4 days, by inclusion of the low dose of 5 mg/day or not, etc.  Or perhaps your doctor likes the Medrol dose-pack, a pre-programmed 6-day tapering schedule in a package of tablets clearly laid out with each day’s decreasing dose.  And most recently you may have been sent home with 50 mg/day for 5 days, then stop.  No taper to off, just stop

As you might surmise, such a variety of approaches reflects lack of scientific knowledge.  The best way to prescribe a short course of oral steroids has not been carefully studied in scientific trials, and it may be that there is no one “right way” to use steroids.  Some people and some exacerbations of asthma may require more medicine for longer periods of time, others may do well with less medicine for shorter duration.  A recent experiment among more than 300 people with chronic obstructive pulmonary disease (COPD, the chronic obstructive lung disease of cigarette smokers) found that 5 days of prednisone at 40 mg/day was as effective as a two-week course of treatment [Leuppi, et al., Journal of the American Medical Association 2013; 309:2223-31], but COPD is not asthma.  It is uncertain whether the same outcome would hold true among persons experiencing flare-ups of their asthma.

What we do know may surprise you.  Despite the time-honored approach of reducing the dose of prednisone in stepwise decreases – the “steroid taper” -- research has shown that abrupt discontinuation of oral steroids achieves the same asthma control and prevention of recurrences as a slow steroid taper, as long as after the oral steroids you continue preventive treatment with inhaled steroids.  When used for a brief period (fewer than 2-3 weeks), there is no medical reason that the dose of oral steroids has to be slowly decreased.  It is o.k. to reduce the dose in stepwise fashion, but it is not necessary for biologic reasons.

In the absence of scientific data, we are free to share with you what we think is a reasonable general approach, acknowledging that other recommendations may someday be found to be just as good or even better (in which case we will change our approach!).   During a severe asthma flare-up we begin with prednisone between 40 and 60 mg/day (40 mg/day for smaller people, 60 mg/day for larger people).  The tablets can be taken altogether in a single, once-a-day dose.  It then makes most sense to continue treatment at this dose until you are all better or almost all better (as guided by your symptoms or, even better, by finding that your measured peak flow has returned back to its usual value when you are well), and then stop the prednisone or quickly reduce the dose to zero over a few days.  Typically, your medical provider will make a guess as to how long it will take for you to recover from your asthma attack and prescribe a specific duration of treatment.  A severe asthma flare usually abates with treatment over 1-2 weeks; milder attacks resolve more quickly.  Sometimes your provider will allow you to adjust the duration of treatment on your own according to your response to it.  Once you are better, we anticipate that you will continue to feel well and maintain good lung function if you continue taking your inhaled steroid and, where possible, avoid the triggers that set off your asthma attack in the first place.

Bidding a Final Goodbye to Asthma Inhalers That Use CFCs as Propellants

As an asthma sufferer, you may find yourself with dual loyalties.  On the one hand, you want to protect the environment for your own health and for the sake of future generations inhabiting this planet.  On the other hand, you want to maintain good asthma control so that you can breathe.  Although there shouldn't be any conflict between these two goals, you may have sensed that there has been ever since pharmaceutical manufacturers started eliminating asthma medications using chlorofluorocarbons (CFCs) to propel the mist from your inhalers.  CFCs are harmful to the environment.  Together with similar molecules formerly used in refrigeration and air conditioning, CFCs interact with gases high in the atmosphere above us, depleting ozone from the stratosphere.  Enlarging ozone holes in the atmosphere and the role of CFCs in causing their formation were discovered by scientists in the 1980s, and by 1989 countries around the world agreed to stop manufacture and sale of most CFCs.  Slowly we have seen elimination of CFCs as propellants for our metered-dose inhalers.

First came albuterol.  Albuterol-CFC was replaced by albuterol-HFA, which used an environmentally-safer propellant called hydrofluoroalkane.  Initially, one pharmaceutical company released its albuterol-HFA inhaler, then came others.  We now have three: ProAir-HFA, Proventil-HFA, and Ventolin-HFA.  It was not a happy transition.  Because there is no generic albuterol-HFA, the cost of these quick-relief medications jumped dramatically.  There was the widespread perception that the new inhalers did not work as well as the old albuterol-CFC inhalers, although careful scientific comparisons between the old and new could find no differences.  And finally, the new medication has a tendency to stick where the metal canister sits in plastic holder, clogging the mechanism and requiring periodic cleaning of the device so that the medication is released freely.

Since then, other asthma medications have been released as metered-dose inhalers with HFA propellants, including the steroids beclomethasone (formerly Beclovent and Vanceril) as Qvar-HFA, fluticasone as Flovent-HFA, and newest among them, ciclesonide, as Alvesco-HFA.  However, not all medications made the transition to the new propellant.  The inhaled steroids, triamcinolone (Azmacort) and flunisolide (Aerobid), simply disappeared from the market, as did the once widely used anti-inflammatory medication, cromolyn (Intal).  Other manufacturers released their asthma medications not as metered-dose inhalers at all but in a dry-powder formulation.  The inhaled steroids budesonide (Pulmicort), fluticasone (Flovent), and mometasone (Asmanex) are available as multi-dose dry-powder inhalers.

This summer marks the end of the road for CFC-driven inhalers.  The last two are both quick-acting bronchodilators -- albuterol plus ipratropium in the Combivent inhaler (more often used to treat COPD than asthma) and pirbuterol in the Maxair Autohaler.  Maxair will simply be withdrawn from the market; Combivent is being released using a novel delivery system, called a "soft mist" inhaler (Combivent Respimat).  This latter new system is a tribute to the inventiveness of pharmaceutical manufacturers as they work to make inhaled medications available in ways that are both effective and safe for our environment. 

The silver lining in all of this is that globally the amount of CFC-type chemicals in the atmosphere decreased by approximately 10% between 1994 and 2008.  It is predicted that the ozone hole over the Antarctic will decrease in size by 2015 and may completely recover by 2050.  We care about the protective ozone layer in our planet's atmosphere because its depletion is associated with increased exposure to ultraviolet light (UVB) on the planet's surface, increasing our risk of skin cancers and cataracts and potentially causing damage to crops and sea life.  With the help of scientific expertise, global cooperation, and some flexibility on our parts, it may be possible to "have our cake and eat it too," or in this case, to protect "spaceship earth" and breathe freely too.

 

Asthma and Binkies. Really?

Did you happen to catch the report that the children of parents who clean their baby’s pacifier at least some of the time by licking it clean in their own mouths have less allergy than the children of parents who clean the pacifier exclusively by washing it with tap water or sterilizing it in boiling water before returning it to the child’s mouth?  Could it be that a parent’s germs are good for preventing eczema and asthma?  Who thought to make that observation … and why?

Researchers in allergy, gastroenterology, and infectious diseases/microbiology at the University of Gothenburg in Sweden conducted this study among just over 100 mother/baby pairs.  (It has been published in the medical journal, Pediatrics, and you can find it on-line at http://pediatrics.aappublications.org/content/early/2013/04/30/peds.2012-3345).  The authors knew of the evidence that when the normal germs that live in the intestines are limited in variety, children are more prone to develop allergies.  Among the evidence is the observation that children who are delivered vaginally – and exposed at birth to their mother’s normal vaginal and possibly fecal germs – are less likely to go on to develop allergies than babies delivered by cesarean section in a sterile operating room.  The researchers wondered about the potential influence of the normal germs that live in the mouth, and whether by sharing their saliva, parents might expose their babies to a broader array of normal bacteria.  The thinking is that if a child’s immune system is exposed to many different types of bacteria at a young age, it will come to accept these foreign substances (antigens) as “friend, not foe” and not attack them using our immune defenses.  Exposure to a broad variety of germs appears to “teach” the developing immune system to accept not only these antigens, but also the harmless ones that we identify as allergens, such as cat or dog dander, dust mites, or grass pollens. 

In this study from Sweden, most (80%) of the children had at least one parent who was allergic, making it more likely that at least some of the babies would develop allergy.  Evidence for allergic disease in the infants was assessed by a pediatrician, based on evidence for sensitization to common allergens on blood testing and the development of asthma or the allergic skin rash, eczema.  Their finding?  When parents cleaned the pacifier by sucking it, their children were less likely to have eczema and asthma at age 18 months; the odds were reduced by more than 50%.  When evaluated again at 36 months of age, the children of parents who cleaned the pacifiers by sucking them still had less eczema, although the differences in rates of asthma and of sensitization to common allergens was no different between the groups. 

Two other findings from this study: first, the number of respiratory infections during the first 6 months of life as reported by the parents did not differ between groups; and second, analysis of the babies’ saliva at 4 months, using a sophisticated technique to analyze the presence and variety of bacterial DNA, showed clear differences between children whose parents did and did not use the sucking technique to clean off their baby’s pacifier.

This study taken alone proves very little, and it certainly cannot be taken as a recommendation for preferred child-rearing techniques.  But it does add to the growing body of evidence that “too clean” (that is, germ free) may have an undesirable effect on our immune systems, contributing to the ever-increasing prevalence of asthma and allergies in our society.  This concept is referred to broadly as the “hygiene hypothesis,” which suggests that reduced exposure of very young children to germs is a risk factor for their development of allergic disease.  Other observations like this study of “binkies” provide additional circumstantial evidence about the yin-yang of germs and allergies.  For instance, going to daycare at an early age, having older siblings, and growing up in close contact with farm animals all have been shown to lessen one’s chances of developing asthma. 

Still ahead is the research that will unravel the exact mechanisms by which the immune system is directed away from allergies when exposed to a broad array of harmless germs at a young age.  The potential impact of this understanding is great.  Some day one might be able to introduce benign germs of the right type in a way -- at the right age, in the right amount, and over the right period of time – such that one could help prevent susceptible children from developing allergy and asthma.  That is the “golden ring” promised by advocates of the hygiene hypothesis.

One Inhaler or Two?

In the U.S. most persons with more than occasional symptoms of asthma have two inhalers: one taken regularly to suppress airway inflammation and prevent asthmatic attacks, the other to be used “as needed” when symptoms of asthma flare.  One is the “controller,” the other the “quick-reliever.”  In most instances, the controller inhaler provides no immediate relief of asthma symptoms, and the quick–reliever inhaler provides no long-term benefit to quiet the inflamed airways. 
One can quickly see the potential for confusion.  “Which inhaler did the doctor say I should take every day, which one only when I was short of breath or wheezing?”  The two inhalers may look virtually identical, except for color.  For other people, the complexity relates to two different types of inhalers.  In the U.S. all of our quick-relievers come in the form of metered-dose inhalers – a metal canister in a plastic holder from which a short “puff” of medication is released.  However, the controller inhalers may take the form of dry-powder inhalers, which require a forceful inhalation to pull the powdered medication from its canister.  Then there is the issue of frequency of use: most controller inhalers are meant to be taken once or twice a day and no more; the quick-reliever can be used up to four times a day and even more often in an acute crisis.

What if ….?  What if there were one inhaler that could be used both as a controller and as a quick-reliever, for maintenance and for rescue?  One device, one technique to be mastered in order to inhale the medication optimally.  Use it once or twice to a day to keep your asthma quiet, use extra doses from the same inhaler if you find yourself short of breath or wheezing.  Such an inhaler, containing a combination of two medications, is available … although in the U.S. it is not recommended for use in this way … yet.

What made this single inhaler for both maintenance and rescue possible was the development of a bronchodilator that both exerts its effect quickly (within 3-5 minutes) and also maintains its effect all day (or night) long.  This medication is the long-acting bronchodilator, formoterol, which works for at least 12 hours to hold open the bronchial tubes, but with an additional dose acts as a quick-reliever.  It is combined with an inhaled steroid in the two inhalers, Symbicort and Dulera.  Symbicort combines formoterol with the anti-inflammatory steroid, budesonide; Dulera combines formoterol with the anti-inflammatory steroid, mometasone. 

Taken every day, these combination steroid/long-acting bronchodilator inhalers can keep asthma under good control.  If asthma flares up, additional doses provide quick relief and at the same time escalate the amount of controller medication, until asthma again quiets.  A recent study published in Lancet Respiratory Medicine confirmed prior reports that this approach is effective and, in the long run, may help to keep the dose of inhaled steroids as low as possible, which is a good thing.

So why have U.S. physicians not embraced this approach?  First and foremost is the lingering concern, previously discussed in this blog (see "The Contoversy That Won't Go Away"), that in some patients long-acting bronchodilators like formoterol may on rare occasion lessen asthma control and cause severe, even fatal asthma attacks.  Although some would argue that the long-acting bronchodilators are potentially dangerous only when used without an accompanying inhaled steroid, definitive research to test this hypothesis is currently being conducted and the results are years away.  Other concerns relate to potential side effects from overuse of a long-acting bronchodilator: if jitteriness or heart racing develops, the side effect will likely last for many hours. 

We do not anticipate that practice will change in the U.S. any time soon.   For now, we are committed to two separate inhalers: one used regularly for control of asthma; one taken as needed for quick relief of troublesome symptoms.  But depending on the results of current research into the long-term safety of long-acting bronchodilators when combined with an inhaled steroid, a small revolution in asthma care may be coming down the road.

Should I Worry About Taking Azithromycin?

Azithromycin is one of the most widely used antibiotics in the United States.  In 2011 more than 40 million Americans received a prescription for azithromycin (Zithromax; Z-pak; Zmax).  Recently, the Food and Drug Administration distributed a drug safety announcement regarding the risk of azithromycin in causing fatal heart arrhythmias (irregular heart beat).  Should we now stop using azithromycin?

Here's how this drug safety warning came about.  Last year researchers reviewed the electronic records of Medicaid patients in Tennessee.  They found that persons receiving a short course of azithromycin were more likely to suffer death from cardiovascular disease, especially sudden death thought due to heart arrhythmia, than persons not receiving antibiotics or receiving an alternative antibiotic, amoxicillin.  If you were a person with no special risk for cardiovascular disease, then the increased risk of dying while taking azithromycin was approximately 1 in 111,000.  If you had serious underlying cardiovascular disease or a tendency to develop heart irregularity, the excess risk of dying while taking azithromycin was 1 in 4,000.  To put this in perspective, your risk of dying from a bolt of lightning is estimated at 1 in 84,000, and your risk of dying in an automobile accident is estimated at 1 in 100.

There are two classes of antibiotics that are known to predispose to irregular heart rhythms.  These are the family of antibiotics called macrolides (including azithromycin, clarithromycin [Biaxin], and erythromycin) and fluoroquinolones (including ciprofloxacin [Cipro], levofloxacin [Levaquin], and moxifloxacin [Avelox]).  The study cited above found that the risk of cardiovascular death when taking levofloxacin was the same as when taking azithromycin.  It also found that the risk of death from cardiovascular disease did not persist after the course of antibiotic.

Our take on this evidence? 

1.   The evidence suggesting that azithromycin can stimulate fatal heart arrhythmias is compelling and believable. 

2.      Will we continue to prescribe azithromycin for our otherwise healthy patients and family members for bacterial respiratory tract infections?  Yes.  Antibiotics remain among the relatively few drugs in our medical toolbox that can cure disease.

 

3.      People who should avoid azithromycin (and other macrolide antibiotics) and levofloxacin (and other fluoroquinolone antibiotics) are those with a known tendency to a particular type of irregular heart rhythm of the ventricle (ventricular arrhythmia) caused by slow electrical repolarization of the heart muscle, manifesting as prolongation of the QT interval on electrocardiogram.  Your doctor will know if you have “prolonged QT syndrome” or are taking other medications that might cause a prolonged QT interval, especially heart medicines such as dofetilide, amiodarone, or sotalol.  A very low blood level of potassium or an abnormally slow heart rate might also put you at risk for this type of heart arrhythmia.

4.      Is this evidence one more reason that otherwise healthy people with viral head and chest colds should take symptomatic treatment (such as acetaminophen [Tylenol], chicken soup, and tea with honey) rather than unnecessary and unhelpful antibiotics?  Definitely yes.

Asthma and Your Bone Health

Asthma is a disease of the lungs, not the bones. There are no bones in our bronchial tubes, right? So where is the connection?


The most important connection relates to the anti-inflammatory steroids ("corticosteroids") used to treat asthma. Prednisone and methylprednisolone (Medrol), if taken regularly or for many months of the year, can have major effects on the bones. In children they can impair bone growth, leading to lesser height as an adult. In adults steroids can decrease bone mass and predispose to the thinning of the bones called osteoporosis. Osteoporosis is a condition without symptoms but one that predisposes to fractures, sometimes with minimal or no trauma. Osteoporosis can cause vertebrae to collapse in on themselves (vertebral compression fractures), ribs to break with coughing or twisting, and hips to break when we fall.

Because of these and many other negative effects of corticosteroids taken as tablets (and distributed via the bloodstream to all parts of the body), safer alternatives to treat the inflamed airways of asthma were developed. In the 1960s corticosteroids that could be delivered directly to the bronchial tubes in the form of medication aerosols became available. The first widely used formulation was beclomethasone by metered-dose inhaler. Since then other corticosteroid preparations have become available, some as metered-dose inhalers, some as dry-powder inhalers, and one as a solution for nebulization. These medications are given in a small fraction of the dose of oral steroid tablets, and only a small portion of the inhaled medication makes its way into the bloodstream, to be carried to the bones and elsewhere throughout the body. As a result inhaled steroids are far safer for the bones than oral steroids.

And yet. A small portion of the inhaled steroid can be absorbed into the blood and carried to the bones. If the dose of inhaled steroid is high enough and the duration of use long enough, it is possible that over a period of several years steroids by inhalation, like steroids swallowed as tablets, can have some effect on bone health. And for many people, it is not an either-or proposition. Many people require daily inhaled steroids for control of asthma plus occasional bursts of oral steroids to reverse flare-ups or asthma attacks.

The potential risk to your bones from long-term use of high doses of inhaled steroids does not mean that you should stop using your steroid inhaler. In most instances, inhaled steroids prevent or reduce the need for oral steroid tablets, which have a far greater impact on your bones. Rather, it means that we -- patients and healthcare providers alike -- need to be vigilant about maintaining good bone health. Regular weight-bearing physical activity is a good place to start to strengthen our bones. Adequate intake of calcium and vitamin D, either in our diets or as dietary supplements, is important "fuel" for our bones. Also, several prescription medicines are available that can slow the development of osteoporosis and even reverse it.

Your healthcare provider can help you assess your risk for low bone mass. He or she may recommend measurement of your bone density with an X-ray specifically designed for this purpose, called bone densitometry or a "DEXA" scan (dual-energy X-ray absorptiometry scan). Persons at risk for osteoporosis (especially -- but not only -- thin women following menopause) are typically screened with bone density X-rays approximately every two years. Remember: good breathing and good bone health are both achievable.