Asthma Blog from the view of an asthma researcher, doctor, and mom

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Why are vitamin D levels so low in Taiwan?

As I’ve talked to physicians in Taiwan, I’ve learned that asthma is even more common in Taiwan than in the U.S.. More than 20% of first graders in Taipei have asthma.  I’ve also learned that vitamin D deficiency is quite common.  I heard one statistic that 40% of children in Taiwan have vitamin D deficiency and an additional 50% have vitamin D insufficiency.

Naturally, I’ve wondered about a connection between vitamin D deficiency and asthma in Taiwan.  Many people have asked me how people in Taiwan could be vitamin D deficient when there is no shortage of sunshine on this island that is close to the equator.

Here’s my answer in pictures to why vitamin D deficiency is common in Taiwan.

1. Men and women avoid the sun by carrying umbrellas (or at least wearing a hat).

2. There are plenty of playgrounds around Taiwan, but I’ve never seen a child playing on one.

3. The car windows have curtains.

4. Drivers wear wrist covers to avoid getting sun on their arms.

5. The milk isn’t fortified with vitamin D.

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Should asthma medications be available for over-the-counter use?

I did it just to see if I could.

I walked into a pharmacy in Taipei and asked to purchase a fluticasone inhaler.  The pharmacy tech brought out fluticasone (50mcg/actuation) which cost $200 Taiwanese dollars which is the equivalent to US$6.67. This is substantially less than my copay of $30 in the U.S. where a fluticasone (44mcg/actuation) inhaler’s average wholesale price is $163.

So I bought the inhaler because I could. And it was cheap.

In light of the ease of purchasing controller medications for asthma relatively easily without a prescription in Taiwan, I read a recent debate on whether certain asthma medications should be available over the counter with great interest.  In Annals of ATS, two articles were published representing pro and con views of this issue.

In the “pro” article, Joe Gerald MD PhD and coauthors argue that making certain asthma medications are more likely to benefit patients than cause them harm. Their arguments include the following:

  • Adherence may improve. Patients spend 2-4 hours of time traveling to, waiting for, and completing physician office visits to obtain a prescription. Being able to buy asthma medicines over the counter could save time and hassle.
  • Physicians benefit economically by keeping asthma medicines prescription only because physician office visits would decrease if asthma medicines were available over the counter. This is a potential conflict of interest for physicians in providing their viewpoint on this issue.
  • Leukotriene antagonists and inhaled corticosteroids are generally quite safe. These medications are safer than existing nonprescription treatments that have minimal efficacy and substantial harms such as children’s cough and cold medicines.
  • The general public and many individual physicians appear to be comfortable with nonprescription medication use.    
  • Prices of the medications are likely to decrease if they were made over the counter. For example, the prices of both Claritin in the US and Zocor in the UK dropped after they were made over the counter.
  • It’s untrue that physician-directed management is superior to other strategies as the BASALT trial found that neither physician- nor biomarker-based adjustments were superior to patient-directed changes.

In an opposing article, Laura Milgram MD examines negative consequences that could result from making asthma medications over the counter. These arguments include:

  • This proposed change would be in direct opposition to national asthma guidelines.  Changing asthma medications to over-the counter status may undermine the importance of initial and ongoing medical interaction for both diagnosis and management of asthma. Migram argues that the lack of attention to other non-pharmacological aspects of asthma management would have the unintended consequence of increased exacerbations.
  • Increased use of nonprescription bronchodilators for asthma could be associated with underutilization of controller medications such as inhaled corticosteroids.
  • Patients may not appreciate the severity of their illness. Thus they may seek out over the counter medications in the situation of acute respiratory distress when they need to see a physician.
  • The costs to the patient of the asthma medication are likely to increase as many medications that become over the counter are no longer covered by insurance.
  • Although beta agonists and inhaled corticosteroids have generally favorable safety profiles, they are not completely benign.

And what do I think?

I’m with the “pro” group that supports making certain asthma medicines over the counter. The medicines are generally safe, no less safe than many over-the-counter medicines. Anectodally, many people already share asthma medicines between children or relatives; so, it’s really no different than being able to purchase these medicines over the counter.

While guidelines suggest a more comprehensive approach to asthma management that does not include only pharmacologic treatment, the reality is the guidelines need to be revamped. The guidelines are not being routinely followed.

And I disagree that we will see an overuse of albuterol or controller medicines. In the same pharmacy in Taipei, I was able to buy albuterol, montelukast, and inhaled steroid/long acting beta agonist (Seretide) at similarly cheap prices.  Despite easy availability in Taiwan, there is no overuse of albuterol or the controller medicines. In fact, there is underuse.

So what is going to happen? In 2012, the FDA proposed a paradigm to allow specific prescription-only medications to be made available for nonprescription. The belief of the FDA was that decreasing the monetary and non-monetary costs associated with obtaining prescriptions would increase medication access.  However, the American Thoracic Society challenged this paradigm and suggested that unsupervised use of prescription-only medications may place patients at risk.

Two recent decisions have been made by FDA advisory Committees.  First, the request to market Primatene HFA to patients with asthma was denied. Secondly, another FDA advisory committee voted against Merck’s request to market Singulair to adults with allergic rhinitis.

It doesn’t look like we’ll be buying asthma medicines over the counter anytime soon.

Filed under medications

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Another possible mechanism explaining the link between statins and reduced asthma exacerbations

In a letter to the editor in response to a manuscript co-authored by Sze Man Tse, MD MPH and me about the association of statins and decreased exacerbations from asthma, Dr. Chang and Dr. Shin propose an additional plausible mechanism. We very much appreciated their comments and prepared a reply that is quoted below and published in the American Journal of Respiratory and Critical Care Medicine.

Dr. Chang and Dr. Shin proposed another mechanism through which statins may reduce asthma severity, namely the antioxidative effect of statins on lipid peroxidation in the lungs.

Although the pleiotropic effects of statins have been highlighted in several studies, the mechanisms through which statins exert these effects are unclear and likely multiple in nature. One of the mechanisms discussed in our article is the antiinflammmatory and immunomodulatory effects of statins. Statins have been shown to inhibit proinflammatory cytokine expression from T-cells and reduce pro-inflammatory cytokine production such as interferon-gamma and IL-5. In murine models of asthma, simvastatin also modulates IL-13 inducible cytokines. Taken together, these immunomodulatory effects potentially reduce pulmonary inflammation.

We agree with Dr. Chang that statins may exert their beneficial effects through other mechanisms. Oxidative stress plays an important role in the pathogenesis of asthma, especially in the setting of acute exacerbations. Environmental factors, such as air pollution, have been associated with release of reactive oxygen species by neutrophils in the airways, with some individuals more susceptible than others. Interestingly, statins have been shown to upregulate plasma levels of antioxidant enzymes such as glutathione peroxidase and superoxide dismutase in patients with type II diabetes, attesting to the direct scavenging effect of statins on free radicals. To our knowledge, these studies have mostly been performed for cardiovascular diseases and diabetes, but not yet in asthma.

Several clinical studies have reported beneficial effects of statins in different lung diseases, including asthma, acute lung injury and lung cancer, with ongoing clinical trials in these fields. However, we have limited knowledge about the mechanisms behind the pleiotropic effects of statins. Better understanding of these mechanisms will not only shed light on the pathogenesis of asthma, it may also allow the identification of novel therapeutic targets.

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CRISPLD2 As a Gene That May Modify Glucocorticoid Responsiveness in Asthma

Today’s guest post is from Blanca Himes PhD, an Assistant Professor at Harvard Medical School.  She writes…

Glucocorticoids are common anti-inflammatory medications that are used to treat many inflammatory diseases. Because glucocorticoids have effects in many tissues, administering them systemically often leads to undesirable side effects. This is one of the reasons that inhaled corticosteroids were developed for the long term treatment of asthma: so that lung tissue could be targeted directly.

Glucocorticoids exert their effects by directly mediating changes in the level of transcription of various genes, and therefore, measuring transcription changes in cells/tissues in response to treatment with glucocorticoids may help to identify disease-specific gene expression changes and, potentially, disease-specific treatment targets. 

For many years, RT-PCR and real-time RT-PCR have been used to measure transcription changes for handfuls of genes at a time, and for over 10 years, gene expression microarrays have allowed us to do this for tens of thousands of genes at a time.

More recently, sequencing technology has been developed to directly identify and quantify levels of transcript fragments that are present in a cell or tissue. This technique, called RNA-Seq, has several advantages over previous technologies, but is still comparatively expensive both because the technology itself is more costly and because analysis of RNA-Seq data requires more sophistication than that of previous techniques. 

Among the tissues that glucocorticoids target in the lung for the treatment of asthma is the airway smooth muscle, a tissue that is directly involved in airway contractility. In a paper published last week, we used RNA-Seq to measure changes in airway smooth muscle cell gene expression in response to treatment with the glucocorticoid Dexamethasone.

In addition to identifying well known glucocorticoid-responsive genes, we identified novel targets, including CRISPLD2. We focused on this gene in further experiments and found that its protein levels are also increased in the airway smooth muscle in response to glucocorticoid treatment. Next, we found that CRISPLD2 expression is also induced by IL1β, a pro-inflammatory cytokine that is often used to simulate an asthma-like state in vitro. At baseline, IL1β induces the expression of other inflammatory cytokines, including IL6 and IL8.

We found that CRISPLD2 knockdown increased the IL1β-induced levels of these two inflammatory genes even further, suggesting that CRISPLD2 may regulate immune response. While our study provides some evidence that CRISPLD2 regulates immune response that may be relevant to asthma, further experimental studies are necessary to pinpoint the mechanisms by which it does so, determine whether CRISPLD2 may be an asthma treatment target, and determine whether its role is unique to the airway smooth muscle. Our study also provides RNA-Seq data and results that can be used by other researchers to understand the effects of glucocorticoids on human airway smooth muscle.

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Do doctors inherently feel like they have to fix things?

I couldn’t pinpoint why I felt so helpless.  One of my favorite people, Maki, a friend from high school and college, was diagnosed with non-small cell lung cancer in 2008.  Since then, I became awkward around her. I think and worry about her 1000x the amount I talk to her.  

Here’s a brief summary of Maki’s story, a beautiful success story for a wonderful person, and the field of pharmacogenomics.

-2008: She was diagnosed with nonsmokers lung cancer diagnosis (stage 3b-which is quite advanced).  She started Tarceva, and miraculously the tumor shrank. She had an upper left lobectomy.

She  beat cancer.

-2009: She started a new job.

-2010: She went off of Tarceva after 2 years with no signs of disease. She completed a triathalon.

-2011: She gave birth to a beautiful baby girl with a big personality. Like her.

-2012: She experienced a recurrence in her lower left lobe and has a small wedge resection surgery. 

She beat cancer again.

-2013: She had another recurrence in lower left lobe.  She wrote a verse of ‘Hello Tarceva, my old friend. I’ve come to take you once again’ and restarted Tarceva. She had a wedge resection surgery (removing ½ of lower left lobe) and endured a terrible post-surgical staph infection. 

But luckily, she beat cancer again.

Recently, she had yet another recurrence in lower left lobe and underwent a completion pneumonectomy. She made this decision with the help of her doctors, but she and her husband were true partners in the decision.

After the most recent surgery, I finally shared with a non-physician friend that I couldn’t understand why I felt so unsettled.  I didn’t know what to do for Maki. I spent so much time thinking about what to do and emailing various experts in the field, but then I didn’t do anything.  

And then my non-physician friend let me off the hook. She told me I just needed to be a friend. I didn’t need to find a cure or do anything.  Just act like everyone else and bring over a chicken-pot pie, she told me. I don’t need to try to fix anything.

And now I feel so much better. As Maki beats cancer once again, I can cheer her on as a friend. Not as someone who thinks she’s supposed to help the medical part of things when she has no expertise, or really any knowledge, about non-small cell lung cancer.

Let’s go, Maki!

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Is it time to revise U.S. national guidelines for asthma?

Click on this link to see my story on Storify using tweets, or read below. 

The U.S. national guidelines for asthma management were last revised in 2007.  It’s become clear to me that many providers don’t follow the suggestions of the guidelines. Even if the provider follows the guidelines, many patients don’t follow the recommended management. The guidelines are based on evidence from well-done studies, and I am strong believer of evidence-based medicine, while focusing on the needs of a particular patient.

If the guidelines were followed perfectly, would we be able to significantly diminish morbidity from asthma? Maybe.  But it’s also possible that the expectations of the guidelines set the bar too high.  I’m questioning whether the guidelines need to be revamped to account for what is actually being done and what patients and providers really think is feasible.
So I asked on Twitter, Is it time for revised national guidelines for asthma? What would you want to see?
Here’s the response:  Yes! Guidelines need to be revamped.


Thoughts for revamping the guidelines include:

1.  Focus on what patient’s care about.

2. Add more detail on how to treat acute asthma exacerbations. (Current guidelines focus on prevention, which is also important.)

3. Start with combination therapy.  (I’m not sure I agree with this. Why risk side effects with multiple medicines that might not be needed?) Current guidelines recommend starting with inhaled steroids (Flovent, Pulmicort, etc) as the first-line controller medicine. I’ve learned from my research and anecdotally that many providers start with combination inhaled steroid/long acting beta agonist (LABA) (Advair, Symbicort,etc). This is even more commonly done in Japan, Germany, Australia, Kuwait and other countries.

4. Develop personalized treatment for each patient would be helpful in the future.  This might with the field of pharmacogenetic research.

5. Simplify the asthma action plan, which is supposed to outline the patient’s asthma medicine regimen.

6. Remember objective tools such as lung function are still important. Current guidelines recommend monitoring peak flow and lung function, but many don’t follow these guidelines.

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Association between antibiotics and asthma

Today’s guest post is from Mei-Sing Ong, Postdoctoral Research Fellow at the Centre for Health Informatics, Faculty of Medicine, UNSW in Australia.  I asked her a few questions about a recent article she published in Annals of Allergy, Asthma, and Immunology.  Along with co-authors, Dr. Ong studied the association between antibiotics and asthma.

The Centers for Disease Control and Prevention estimates that almost 7 million children—nearly 10 percent of all children in the U.S.—currently have asthma. And U.S. pediatricians fill out upwards of 50 million antibiotic prescriptions for kids every year. .

Looking at claims for the more than 62,500 children, Ong and co-authors found a strong association between antibiotic use before age 1 and early onset of asthma before the age of 3 years. On average, children who were given antibiotics in the first year of life were 2.5 times more likely to develop asthma by age 3 than children who weren’t. And the more antibiotics a child received, the higher a child’s asthma risk.

I asked Dr. Ong the following questions: What was the goal of your study, what did you find, and what are the implications?

She writes…

As you probably know, our study is not the first to examine the relationship between antibiotic use in infancy and asthma. However, most previous studies were confounded by early-life respiratory infections, which are both a risk factor of asthma, and a reason for prescribing antibiotics. The goal of our study is to really try and disentangle these relationships. We were able to do that using our very large dataset. We assessed the risk of asthma in children with and without early-life respiratory infections, and found an elevated risk of asthma among children exposed to antibiotics in both groups. 

Interestingly, the effect was only seen in asthma that precipitated before the age of 3. In half of these children, early asthma was transient and resolved by the age of 3; in the remaining children, early asthma persisted after the age of 3. Previous studies have alluded to the existence of different asthma phenotypes, late-onset asthma tend to be non-atopic. So it is possible that antibiotic exposure is associated with allergic asthma, and not non-allergic asthma. 

I see our study as just another piece of a largely incomplete puzzle. The concept of asthma phenotypes is still evolving. We have tried to account for known confounding in our study, but there may be others that we have not accounted for, including early-life infections that did not result in a doctor visit. Nonetheless, I think unnecessary use of antibiotics should be avoided. 

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My daughter and my interview about Wellapets asthma game

See Allison and my interview about the Wellapets asthma game here.  My kids really do continue to play the game, and Allison’s playing led a recent house guest to download the game as well.

This interview is being shown in hundreds of news stations across the country.  Here’s the text…

Nine-year-old Allison Wu is an avid gymnast, but sometimes her asthma can make her body feel off balance.

"Normally I start to cough a lot, and sometimes it bothers my throat, and when it really bothers me, I start to wheeze," she said. 

A new video game, called Wellapets, uses virtual pets to help kids with asthma understand and manage it.

A lovable fire-breathing dragon becomes the child’s pet. The only way to help him blow fire is to properly manage his asthma. 

"I learned about that, like, cockroaches and smoke are not good," said Allison.

As a mother and pediatrician, this is one video game Allison’s mom wants her to play. 

"She’s learning how to take ownership of her own illness and not needing me for everything," said Ann Wu. 

The game also teaches children about asthma triggers, like smog, and reminds children how and when to use their medication properly.

"Taking your inhaler with the right technique; taking your controller inhaler at the right time; learning how to avoid triggers; and learning how to recognize your own asthma symptoms and take action for those," Wellapets co-founder and CEO Alexander Ryu explained.

Even those who don’t have asthma are enjoying the game and better understand what their siblings and friends go through.

This virtual pet program is a free app and can be downloaded at Google Play and the App Store. 

LifeGuard Games, the developer of Wellapets, say they plan to roll out a host of games to help manage food allergies, diabetes and other health issues.

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Behavior change techniques to help with medication adherence?

I received the following email. I’m sharing here (with his permission) to see if others have thoughts for Nikos Papchristou.

Dear Dr Wu,

I saw your comment about adherence and I would like to share my point of view. 

I have a feeling that an integration of behavior change techniques (Behavioral Change Wheel, Dr Suzan Michie UCL), tiny micro-habits (Dr BJ Fogg, Stanford) and appropriate mhealth design patterns (I like to call them personalised digital health intervetions) most probably could provide better efficiency on this problem. I believe that we are not there yet because we lack proper design principles & standards and true ubiquitiness of technology. 

Based on the limitations of the human congitive capacity, emotional control and personal environment context I can not think of anything more sustainable for the future (I took under consideration the limitations implied by the current healthcare costs and national economies’ “health” also).

Another point not to forget, because as I wrote it it may cause misunderstandings, is that I do not consider mhealth interventions interventions by themselves. If we could make an analogy with the drug paradigm, mhealth is the inactive ingredients and the behavioral change model/design is the active substance. In every disease/case we try to identify the right type of behavior model and techniques to apply, while mhealth is the mean (different type of device/interface, content, type/rate/rythm/context of feedback) to elaborate these. Without the first part mhealth may not have any effectiveness or essense. The behavioral change wheel and implementation science comes along when we have made something to work in a “controlled environment” and we may want to scale it in more pragmatical and complex situations. 

Kind regards,

Nikos Papachristou

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Higher Health Insurance Cost-Sharing Impacts Asthma Care for Low-Income Kids

Last May, Vicki Fung PhD contributed a post to here.  The manuscript was just published online in JAMA Pediatrics. 

Here’s the summary from JAMA Pediatrics:

Bottom Line: Parents in low-income families were less likely to delay asthma care for their children or avoid taking their children to see a doctor is they had lower vs. higher levels of health insurance cost-sharing.
Background: The Patient Protection and Affordable Care Act (ACA) includes subsidies to reduce cost-sharing for low-income families. Limited information about the effects of cost-sharing on care for children is available to guide such efforts.   
How the Study Was Conducted:  A 2012 telephone survey that included 769 parents of children with asthma (ages 4 to 11 years). The authors examined the frequency of changes in seeking care and financial stress because of costs. Of the children, 25.9 percent were enrolled in Medicaid or the Children’s Health Insurance Program; 21.7 percent were commercially insured with household incomes at or below 250 percent of the federal poverty level (FPL); and 18.2 percent had higher cost-sharing levels for all services (e.g. $75 or more for an emergency department visit).
Results: Parents at or below 250 percent of the FPL with lower vs. higher cost-sharing levels were less likely to delay or avoid taking their children to a physician’s visit (3.8 percent vs. 31.6 percent) and the emergency department (1.2 percent vs. 19.4 percent) because of cost. Parents with higher incomes and those whose children receive public subsidies (e.g. Medicaid) also were less likely to skip getting care for their children than parents at or below 250 percent of the FPL with higher cost-sharing levels. Overall, 2.6 percent of parents reported switching their child to a cheaper asthma medicine and 9.3 percent used less medicine than prescribed because of the costs. Also, 7.6 percent of parents delayed or avoided taking their child to an office visit and 5.3 percent delayed or avoided an emergency department visit because of costs.  Among those who reduced medication use, 41.1% of parents reported that if affected their child’s asthma care or overall control.  Among those who delayed or avoided any office or emergency department visit, 38.1% and 27.4%, respectively, reported that it affected their child’s asthma care or control.  Many parents (15.6 percent overall) borrowed money or cut back on necessities to pay for care for their children.
Conclusion: The ACA’s low-income subsidies could reduce these barriers for many families, but millions of dependents for whom employer-sponsored family coverage is unaffordable could remain at risk for cost-related problems because of ACA subsidy eligibility rules.