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.