Yesterday’s post was about the relationship between infection and asthma. Coincidentally, a 10 year old child with asthma drew this picture for me. She said, “When I have an asthma attack, it feels like clogging in the chest. My chest gets real tight. It feels like germs are going in there.”
So, I told her about yesterday’s post — that infections can trigger asthma flares, but persons with asthma are also more likely to have infections.
Here’s her picture….
The most common trigger of an asthma exacerbation is a respiratory tract infection like the common cold. A recent review article by Young Juhn, MD MPH in the Journal of Allergy and Clinical Immunology highlights new studies that suggest people with asthma and other allergic diseases (eczema, allergies), may be at increased risk of having common and serious infections with both viruses and bacteria.
Infections and asthma and allergic diseases are interrelated in every way.
- Infections could be protective of asthma and allergic conditions.
- Infections such as the common cold (rhinovirus) could provoke asthma flares.
- Infections could be part of the context of asthma and allergic condictions.
Or, the reverse could be true. (focus of this article)
- Asthma and allergic diseases could cause the increased risk of infections.
If all of this were true, persons with asthma could end up in a vicious cycle with the asthma causing infections, which then trigger asthma flares.
This figure is Dr. Juhn’s depiction of the bidirectional causal reltionship between infections and allergic conditions.
Dr. Juhn reviews what is available in the literature currently.
- Patients with asthma, eczema, and allergic rhinitis have increased risk of pneumococcal pneumonia and invasive pneumococcal disease. This is the reason all patients with asthma ages 19 to 64 years are recommended to receive the pneumococcal vaccine (PPV23).
- Patients with asthma also have increased risk of infections with other bacteria such as Strep pyogenes, Strep pneumonia, Staph aureus, etc.
- Patients with asthma have increased risk of Bordetella pertussis infection (which causes whooping cough), Legionella, E.coli infection, and mycoplasma (walking pneumonia).
- There is even an increased risk of non-respiratory tract infections such as urinary tract infections or shingles.
What are reasons for asthma causing increased risk of infections?
- Inhaled steroids (Flovent, Pulmicort, etc) have immunosuppressive properties and are the most commonly used controller medications for asthma, but inhaled steroids do not appear to be the cause. One study suggested that inhaled steroids might actually be protective of lung infections.
- Immunologic abnormalities and dysfunctions that are associated with asthma and allergic conditions might be responsible. This is an important area of active study. Immune dysfunction at every stage from colonization to severe infections appear to be increased.
- It’s known that some asthmatic patients have impairment of innate immunity and this could lead to increased infections as the immune system does not work to its full potential.
- Patients with asthma may have increased colonization of many types of bacteria.
What are Dr. Juhn’s conclusions?
- Asthma patients aged 19 to 64 years should continue to be vaccinated with PPV23 (pneumoccocal vaccine). (Risk of pneumonia is increased and pneumonia could trigger asthma flare.)
- Potential for increased risk of infections should be assessed carefully by clinicians.
My very first blog post (18 month ago!) was entitled, “Asthma Three Ways." In this post, I explained that when you order Peking Duck, some restaurants give you the duck in 3 ways: the Peking Duck and then two more courses. This dish is the inspiration for the title of my blog.
I finally remembered to take photos during a recent family dinner.
First, we had the Peking Duck.
Next, we had stir-fried duck with vegetables.
Third, we had the duck with bones cooked in sesame oil and basil. Often this third dish is a soup so that you really get every ounce of flavor out of the bones.
A study I led was just published online in the Journal of Allergy and Clinical Immunology: In Practice.
The most commonly used medications for asthma are inhaled corticosteroids (Flovent, Pulmicort, etc), leukotriene receptor antagonists (Singulair, etc), and inhaled corticosteroid/long acting beta agonist combination therapy (Advair, Symbicort, etc). Studies have found that inhaled corticosteroids have greater efficacy than leukotriene receptor antagonists to prevent exacerbations of childhood asthma under controlled circumstances. However, few studies have compared the effectiveness of these controller medication regimens under real-life conditions.
In this study, we set out to determine the likelihood of asthma exacerbations after initiation of controller medications among children with asthma—under real-life conditions. Using electronic data from TennCare Medicaid and five large health plans (Harvard Pilgrim Health Care, HealthPartners, Kaiser Permanente Northern California, Kaiser Permanente Northwest, and Kaiser Permanente Georgia), we studied a total of 26,191 children ages 4-17 years with uncontrolled asthma. The main outcome measures were asthma-related emergency department visits or hospitalizations, or oral corticosteroid use in the year after filling a controller medication.
We found that overall adherence to controller medications was low. In patients with allergic rhinitis, subjects in TennCare Medicaid who were treated with leukotriene antagonists were less likely to experience emergency department visits compared to subjects treated with inhaled corticosteroids. For all other groups, the risk of emergency department visits, hospitalizations, and oral corticosteroids did not differ between children who initiated leukotriene antagonists and inhaled corticosteroids. These findings may be explainable by leukotriene antagonists having similar effectiveness as inhaled corticosteroids in real-life usage, by residual confounding by indication, or other unmeasured factors.
Today’s guest blog post is from Ariq Azad from Praxis Health - an online training platform that gives parents the skills and tools they need to manage asthma in their children. He’s looking for enthusiastic parents of children with asthma who want early access to the program and willing to offer feedback.
We started Praxis Health after we realized that there aren’t good online asthma management training resources. As many parents of kids with asthma can attest to, asthma management is difficult, frustrating, and requires a level of training. Parents of asthmatic children need to understand asthma, be able to manage a complex medication regimen, use inhalers correctly, clean up indoor triggers regularly, follow an asthma action plan and on top of all that follow up with their child’s doctor and school. This can be very overwhelming – and because it’s so difficult, asthma remains uncontrolled in the majority of cases.
There exists, however, some very successful Asthma home- based case management programs. These programs send nurses or other health professionals to the patients’ homes for intensive training – and research shows that they have been effective in decreasing ER rates and hospitalizations. One of the difficulties of these programs is that they require in-person home visits, which makes it difficult to reach a lot of families as resources are often limited. Praxis Health is on a mission to digitize these physical training programs as much as possible. Why? By putting the training online and using the latest in education technology, and equipping parents with the tools they need to implement these skills, Praxis Health hopes to train and reach thousands of parents in need.
So, what does the program look like? It is a 3-hour online, interactive course parents can take on their own time. By the end of the course, parents will have the skills needed to: identify and remove indoor triggers, administer medications properly, and use an asthma action plan to stop asthma attacks early. In addition to skills training, parents will be given many tools to help them manage asthma. One tool is a smartphone application to find indoor triggers and another is live video training on proper inhaler technique. We also have a staff of virtual asthma educators who will help you throughout the course and are available to answer any questions you might have.
We are looking for parents to give feedback on the program before we launch it nationwide. If you are a parent of a child with uncontrolled or newly diagnosed asthma and are interested in trying the program, please contact me at firstname.lastname@example.org. In addition to getting early access to this program, you’ll be taking part in the creation of a landmark program and making it better for many parents to come!
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.
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.
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.
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.
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!