Sunday, November 30, 2014

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.

Saturday, November 8, 2014

"... 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.

Tuesday, July 29, 2014

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:

Saturday, April 5, 2014

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.

Monday, January 20, 2014

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!