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.

Can Asthma Turn into Emphysema?

For the most part, asthma and emphysema are two distinct and unrelated diseases. Asthma most often begins in childhood and is closely related to allergies. Emphysema begins in middle age or later and is almost always due to cigarette smoking. Asthma is a disorder of the bronchial tubes, with difficult breathing resulting from swelling of the air tubes and contraction or “spasm” of the muscles that surround those tubes (“bronchospasm”). Emphysema involves destruction of the walls of the air sacs deep in the lungs (the “alveoli”), and as a result, loss of elasticity of the lungs. In emphysema air easily enters the lungs when we breathe in, but slowly empties from the lungs when we breathe out because the springiness or elasticity of the lungs has been lost, like an old rubber band that has lost its recoil.


And the biggest difference between asthma and emphysema is that persons with asthma who are free of symptoms are expected to have normal or near-normal lung function (their bronchial tube inflammation has abated and their bronchial muscles are not in spasm). Persons with emphysema have permanent loss of lung function; even on a good day, the lung damage remains and breathing capacity is impaired.

But … and there always seems to be a “but” when making general assertions about biology … not everyone with asthma, when well, achieves normal or near-normal lung function. Perhaps you are one of those people with asthma who never smoked cigarettes, have no reason to have emphysema, and yet even under the best of circumstances and with maximal asthma treatment still have reduced lung function. You get short of breath more easily than other people when you exert yourself, and tests of your lung function remain far from normal, even when you are doing well. You have a component of permanent, irreversible narrowing of your bronchial tubes. Doctors sometimes call it “fixed” airways narrowing, in the sense of “stuck” or “immovable.” Although you do not have emphysema (destruction of the walls of the air sacs in your lungs), you have a similar problem: a permanent reduction in your breathing capacity.

It is not difficult to envision that some people with asthma might develop scarring in and around their bronchial tubes, and scar formation lasts forever. All the rest seems to be unknown, however: why do some people with asthma develop this permanent airway narrowing and most others not; when does it happen in the lifelong course of asthma; is it always progressive; and is there any way to prevent it? We know that in persons with asthma, permanent airway narrowing is associated with cigarette smoking; and we shouldn’t smoke. What else? Childhood illness resulting in impaired lung growth? Long-term asthma that has been inadequately treated? Recurrent asthmatic exacerbations that cause a “step-wise” decline in lung capacity?  These are all potential explanations, but none is certain; and different people may be affected by different mechanisms.

No, asthma does not turn into emphysema. But, yes, in some persons asthma can result in permanent narrowing of the breathing tubes that might, strictly speaking, be considered a “chronic obstructive pulmonary disease” or COPD. A “holy grail” of asthma research is discovery of the causes of this scarring of the bronchial tubes and its prevention. We are at the very beginning of a long road to discovery and cure.