Tag Archives: Conditions and Diseases

How To Stay Informed

Thanks for following along with the diagnosis and treatment of eosinophilic esophagitis (EoE)–a condition that during my fellowship training in allergy wasn’t even recognized as a cause of abdominal pain. 

Treatment options for EoE are currently:

  • Corticosteroids–both oral and inhaled
  • Dietary avoidance of known allergic triggers, including but not limited to foods 
  • Use of PPIs such as Nexium & Protonix
  •  Treatment principles focus on reducing symptoms and eosinophil counts while, importantly, protecting and preserving quality of life.
  • Maintaining diet and nutrition which is harder than it looks! Don’t forget that restoring growth parameters are also essential for adults as well as in children.
Tastes Great, but NOT less filling!

As with all diseases, treatment is updated constantly, and new recommendations emerge.   As with many inflammatory conditions, steroids work great, but are NOT less filling.  Side effects from steroids are many and any time an alternative is successful, you’re better off.  Remember, topical steroids are fine, it’s the oral systemic absorption of steroids that contributes to the side effect profile.  

 Due to the long-term side effects associated with high dose corticosteroids and a tendency for relapse after discontinuation, this therapy is not first-line outside of using short bursts and tapers for severe symptoms needing urgent relief (eg, critical dysphagia, stricture, dehydration and acute weight loss.

Topical Corticosteroids

Topical corticosteroid are used in EoE through 1 of 2 routes:

  • “Gulping” the expressed actuations of an inhaled device; or
  • Expressing the contents of a nebulizer respule into a cup, forming a thickened slurry by mixing it with sucralose/maltodextrose (Splenda®), and water.

Use in this manner provides “local” or tailored coating of esophageal tissue, at lower doses (220 μg-1 mg per dose). Faubion and colleagues demonstrated that 880 μg/day of swallowed fluticasone propionate or beclomethasone diproprionate resulted in symptomatic improvement in 4/4 pediatric patients Noel and group at the Cincinnati Children’s Medical Center, noted that non-atopic patients had a better response rate to the topical steroid than the atopic patients.  A randomized, controlled trial by Konikoff and colleagues confirmed similar findings independent of pre-treatment eosinophil numbers. 

Oral viscous budesonide (OVB) is quickly becoming the preferred therapy to fluticasone. The technique of swallowing a liquid dose may be more effective and efficient than “gulping” a hydrofluroalkane gaseous suspension. Additionally, OVB has comparable efficacy. One study found an 80% decrease in a symptom scoring index and regression of cell counts to less than 7 Eos/HPF; after 3 months of therapy there was decreased fibrosis/remodeling from baseline.

Dosing for fluticasone ranges from 220 to 880 μg per day, and for budesonide, from 0.5 to 2 mg per day; both doses are similar to those used in asthma. With either agent, patients are instructed to not eat or drink for 30 minutes after administration. Complications from topical treatment include oral/esophageal candidiasis.  In a 3-year case series studying recurrence, approximately 90% of adults relapsed at a mean of 8 months post discontinuation of 6 weeks of therapy. Just like asthma, when you stop using the controller medication, symptoms will come back.  No study of optimal dose or duration of therapy has been performed, but most adult providers recommend a 6-week course while pediatric providers suggest a 12-week course.  No long-term safety data exist pertaining to bone or adrenal effects from such small but more readily bioavailable dosing methods used in EoE.

Acid Suppression

Technically, EoE should not be diagnosed until response to PPI therapy has been determined, according to the 2007 and 2011 consensus guidelines. A certain subset of patients will have PPI-responsive esophageal eosinophilia.  Typically, dosing is either 10-40 mg omeprazole or 15-30 mg lansoprazole per dose for 2-3 months. High-dose PPI therapy may distinguish GERD from EoE.

Immunomodulating Therapy

Immunomodulating therapies may offer some promise. The best studied therapy is anti-IL-5. In mice, anti-IL-5 decreases blood and tissue eosinophils, and decreases eotaxin-3 levels. Garret and fellow researchers studied anti-IL-5 in 4 patients with hypereosinophilic syndrome. Symptoms and eosinophilia resolved, and in 1 patient who also had EoE, dysphagia and esophageal eosinophils decreased. Stein and colleagues, in an open-label phase I study of anti-IL-5, noted that blood eosinophilia was reduced but not correlated to decreased levels of IL-5, eotaxin-3, or esophageal eosinophilia.   Similarly, there was no significant difference between groups in symptom improvement. Studies of other agents, such as anti-IgE or anti-TNF (infliximab), failed to demonstrate any symptomatic or esophageal histologic improvement. Presently, anti-IL-3 is under investigation in a phase 1 trial, but no data are available pertaining to its safety or efficacy.

Dilation

Dilation relieves critical esophageal narrowing and related symptoms, but will not alter the underlying pathophysiology. Its benefit is maximized for dysphagia and impaction from ring/stricture or other critical narrowing. Several studies have demonstrated the efficacy of dilation, though it is balanced by risks including perforation, deep mucosal tears, pain, linear renting, and bacteremia. Relief is also likely to be transient, because 75%-50% of patients who receive this therapy have recurrence at 2-20 months and need additional dilation.

Dietary Management

A 6-week trial of 10 patients conducted by Kellyand colleagues in 1995 demonstrated the role of an exclusively elemental diet.  At the conclusion of the study, 8/10 had complete histologic and symptomatic resolution and the other 2 subjects showed drastic improvement, demonstrating an elemental diet as a potential treatment. As with steroid therapy, however, upon discontinuation, all patients relapsed. A larger study of elemental diet therapy in 51 patients was conducted by Markowitz and colleagues.  The researchers noted symptomatic response by 8 days and normalization in biopsy by 1 month in 49 of the patients studied. Liacouras and colleagues followed 389 patients with EoE over 10 years, 160 whom were treated with elemental diet and noted a 97% response rate to the diet and biopsy counts that were comparatively lower than 75 patients on swallowed fluticasone. Though exceptionally effective, elemental therapy is limited in that a patient’s only source of nutrition is a very specific hypoallergenic formula. This may not be appropriate for adolescents or adults. Some cases require placement of gastrostomy tube to assist with feeding.

An alternative approach is a tailored/guided diet that avoids only an individual’s known food sensitizations based on skin prick and/or patch testing. Spergel and colleagues described 120 patients placed on a guided elimination diet based on allergen testing.  After 6-8 weeks, 112 had near complete tissue resolution, though 39 relapsed upon reintroducing eliminated foods. In this cohort, 77% had at least 1 positive prick skin test, and 85% had 1 positive atopy patch test. Prick skin tests were most commonly positive to milk, egg, soy, and peanut. The foods that were most commonly positive to atopy patch test were corn, soy, wheat, and milk. Most patients were sensitized to multiple foods, and dietary nonresponders had more sensitizations than responders. Positive predictive value and negative predictive value for 13 commonly positive foods in EoE were published in a previous post.

Follow-up of patients with EoE should be frequent, at least 4 times per year, with consideration for repeat endoscopy at those intervals as well. Repeat endoscopy is the only way to monitor disease progress, because symptoms do not always correlate with disease progression. One pediatric study found that an initial cell count of 6 or greater was predictive of a repeat positive biopsy.

 At each follow-up visit, diet should be reviewed, diet/medication compliance assessed, and consideration given for additional food testing if symptoms or histology are not improving. As noted previously, there are no studies that have evaluated adequate or optimal duration of treatment for either dietary avoidance or topical steroid duration. Very little formal guidance is available to determine key long term predictors of disease resolution, the optimal interval for repeat biopsy, and the effect of these factors on the development of long term sequelae.

Complications from EoE include:

  • Strictures,
  • Schatzki ring
  • Esophageal trachealization and stretching,
  • Esophageal furrowing and narrowing, microabscesses, webbing,
  • Food impaction, persistent/progressive dysphagia, and lamina propria fibrosis.

Esophageal remodeling in EoE occurs as a result of subepithelial fibrosis and is reported in 15%-40% of affected adults. Predictors that influence the likelihood of developing fibrosis are presently unknown. To date, there is no identified association with progression to malignancy directly from the presence of EoE. Some have observed a potential link between celiac disease and EoE, which may share some common gene upregulations with EoE, but this association is not well understood.

The natural history of food allergy/sensitization within EoE has not been well-described. Lastly, while preliminary work and observation indicates that quality of life can be affected significantly, little formal study of EoE quality of life exists. This particular area of research is very important to continue to define, as the quality of life issues that affected families face are distinct from those of the general food allergy community.

From the Journal of Allergy & Clinical Immunology (In Practice)

 Informational video on eosinophilic conditions

A Penny for your Thoughts!

Nickel allergy

Nickel allergy very common

can result in both cutaneous and systemic manifestations, and can range from mild to severe symptoms. A severe form of this allergy is the Systemic nickel allergy syndrome, clinically characterized by cutaneous manifestations (contact dermatitis, pompholyx, hand dermatitis dyshydrosis, urticaria) with a chronic course and systemic symptoms (headache, asthenia, itching, and gastrointestinal disorders related to histopathological alterations of gastrointestinal mucosa, borderline with celiac disease). This review aims to briefly update the reader on past and current therapies for nickel contact allergy.

Nickel is the main sensitizer; its prevalence varies from 4.0 to 13.1% in different countries and is still increasing. Nickel allergy is more common among women than among men (17% and 3%, respectively). This difference is due to different rates of exposure of skin to this substance; such exposure (from jewelry, leathers, etc) is more frequent among women.  Makes sense, can I go shopping now! Continue reading

Wedding Ring allergy

Think you can be allergic to your spouse? Just this week in the clinic, a middle-aged woman presents with a rash found only when she wears her wedding ring.  No other jewellery gives her problems except for the ring when worn > 2-3 days.  Although nickel allergy can cause this scenario, this woman probably has occlusion dermatitis or “wedding ring allergy.”  Any accumulation of soap and water underneath the ring will cause this type of dermatitis in sensitive individuals.  Want to learn more? 

http://www.medicinenet.com/script/main/art.asp?articlekey=107570

Are CT scans dangerous?

Research does demonstrate that in children, CT scans can lead to a small, but measurable increase in the risk of cancer.  How does one protect your child, yet obtain the x-rays that will give the proper diagnosis and are clinically indicated?

  1. I am of course referring to a CT (coronal) scan of sinuses used to diagnosis infection or anatomical nasal obstruction.  Many patients need CT of sinuses because the underlying cause of their runny nose has never been identified.
  2. Fortunately, coronal CT of sinuses exposes children to very little radiation because the area that is examined is very small (just the face)
  3. Coronal CT of sinuses does not require repeated examinations.  Once is usually enough!
  4. Usefulness of a plain sinus x-ray is questionable.  False negative rates (study is normal, but wrong) can be as high as 30-40% with a plain radiograph.  Take home message: benefit isn’t worth the risk.

Read the article below, but you probably don’t need to worry about CTs of the sinuses. 

http://www.usatoday.com/news/health/story/2012-06-07/childrens-ct-scans-cancer/55439406/1

Improvement in survival without new drugs!

Truly remarkable how cancer survival has improved in children WITHOUT the addition of new drugs.  There is so much more to health than just taking more medication!  Allergy operates in the same way–good avoidance is first, followed by other aggressive medications.

http://www.usatoday.com/news/health/story/2012-06-04/childhood-cancer-progress/55333892/1

Are We Overreacting?

The Journal of Allergy and Clinical Immunology
Volume 129, Issue 5 , Pages 1280-1281, May 2012

Thanks Dr Pedersen for your insight!  The bottom line: maybe combination Advair, Symbicort, or Dulera aren’t as bad as they are put out to be. 

Over the last decade, the aims of asthma management have altered to focus on achieving and maintaining good asthma control and reducing future risks, such as decrease in lung function, asthma exacerbations, hospitalizations, death, and adverse effects from treatment.  The benefits of good asthma control include a variety of asthma outcomes that are important to both patients and society.

These include:

  • No restriction in lifestyle
  • Better physical fitness and quality of life
  • Reductions in patients’ perception of the asthma burden, health care resource use, and lower risk of exacerbations, hospitalizations, and death.

Inhaled corticosteroids (ICSs) or combination therapy with an ICS and a long-acting β2-agonist (LABA) have become established as cornerstones in guideline-recommended asthma treatment because these therapies have been the most successful in achieving asthma control and reducing future risks in the vast majority of patients with asthma. 

Changes in the goals of asthma management, as well as treatment recommendations, have revolutionized management from both the patient’s perspective and a societal perspective. The main question that remains is whether the clinical benefits balance or outweigh the risks of the treatments?

When regular ICS treatment was introduced 4 decades ago, safety concerns were common, and initially, the treatment was reserved for patients with severe disease. The concerns were based on fears generated by the side effects of oral corticosteroids rather than data generated by using ICSs, but with increasing knowledge and experience, the concerns decreased, and ICSs became a first-line therapy for asthma because the benefits of the treatment clearly outweighed the risks.  Fast foward to 2012 and our concern is overuse of combination therapy with LABAs/ICS as a risk factor for severe, albeit rare, severe asthma exacerbations. 

In this issue of the Journal of Allergy and Clinical Immunology, Wells et al add to the paucity of real-world data by reporting the findings from a large, population-based, real-world observational study comparing the effects of ICSs and fixed-dose ICS/LABA combination therapy on severe asthma exacerbations in a racially diverse population of 1828 patients with a total of 3791 person years of follow-up. Data were obtained longitudinally from a managed care organization, and LABA exposure was estimated from pharmacy data. It was found that ICS/LABA combination therapy had an overall protective effect on asthma exacerbations that was as good as or better than that for ICSs alone. The protective effects of ICS/LABA combination therapy seemed particularly marked in patients older than 18 years, male subjects, patients with moderate and severe asthma at baseline, and reassuringly, African Americans (who have been suggested to be at greater risk).

Although the study is well executed, carefully analyzed, and uses sound methodology, it was not of a sufficient size to make any firm conclusions about severe but rare asthma-related events, such as intubations, death, or both. Yet it is an important contribution to the literature on the perceived risk of serious adverse effects of LABAs. It is reassuring that the results from a carefully executed observational study, mimicking real-world study conditions, are in such good agreement with the findings in the randomized, controlled efficacy trials comparing ICS use alone with a fixed LABA/ICS combination.  In addition to significant improvements in asthma control, such studies consistently report reductions in asthma exacerbations, need for oral steroid bursts, and asthma-related emergency department visits compared with ICS treatment alone. Because such events normally precede more serious outcomes, such as intubations, death, or both, these findings make it unlikely (but do not prove) that treatment with fixed LABA/ICS combinations per se should be associated with an increased risk of these serious outcomes.

The US Food and Drug Administration has requested a series of very large postmarketing clinical trials to evaluate LABA/ICS combination safety, (see reference below) but the most serious asthma outcomes are so rare that even these studies might not be able to provide a definite conclusion. Moreover, the results from these studies will not be available until 2017 at the earliest. What should clinicians do in the meantime?

It would be a disservice to our patients if we, in the fear of doing harm to our patients, waited for the perfect. The study by Wells et al supports that a better option would be to follow the recommendations of the asthma guidelines, which unanimously have taken the stand that there is no convincing evidence that LABA/ICS combinations administered in a single inhaler are associated with serious adverse effects. Their benefits on asthma control and reduction of asthma exacerbations outweigh their risk, and we should be careful not to let the perfect become the enemy of the good.

Chowdhury BA, Seymour SM, Michele TM, Durmowicz AG, Liu D, Rosebraugh CJ. The risks and benefits of indacaterol—the FDA’s review. N Engl J Med. 2011;365:2247–2249

The More You Know, the Less You Know

The practice of medicine is just that….I advise the recommended treatment based on the information available at the time.  If I look back to the time during my fellowship in the early 90′s, much of what we thought was true and now 20 years later, been disproven.  As an example, the following study from a respected medical journal cautions against the use of PPI medication for reflux in children.  It’s worth your attention, but first some background information.

Children have a high prevalence of asthma and gastroesophageal reflux (GER). Children with asthma often report symptoms of GER and also have a high prevalence of asymptomatic GER.  We call this “silent reflux”. 

Some experts have suggested that untreated GER may cause persistent asthma control problems in children refractory to treatment with inhaled corticosteroids. However, whether treatment with proton pump inhibitors (PPIs) improves asthma control has not previously been determined. The objective of this study by Holbrook and colleagues was to determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER.  (ie, Prevacid for “silent reflux”)

Study Synopsis and Perspective

Use of PPIs in children with poorly controlled asthma who were using inhaled corticosteroids and who had no symptoms of GER was not found to improve asthma control and was, in fact, associated with an increase in adverse effects, according to results of a study published in the January 25 issue of JAMA. (PPIs Produce Negative Outcomes in Children With Poor Asthma Control)

PPIs “are often prescribed for poorly controlled asthma regardless of reflux symptoms, and there have been large increases in the use of PPIs among children between 2000 and 2005…. Hence, it is of clinical importance to determine whether antireflux therapy, the most common of which are PPIs, improves control of asthma in children,” write Janet T. Holbrook, MPH, PhD, from the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues from the Writing Committee for the American Lung Association Asthma Clinical Research Centers.

The goal of this placebo-controlled, double-masked, randomized study was to determine whether the PPI lansoprazole was effective in controlling asthma symptoms in children with asthma, but no overt GER. The researchers also investigated whether pH testing would identify children with GER who responded to PPI therapy.

The children were randomly assigned to receive either lansoprazole (15 mg/day for those weighing <30 kg; 30 mg/day for those weighing ≥30 kg; n = 149) or a matching placebo (n = 157). The researchers found that the mean difference in the Asthma Control Questionnaire (ACQ) score between the 2 groups was 0.2 units (95% confidence interval [CI], 0.0 – 0.3 units), which was not statistically significant (P = .12).

There also was no significant difference in the forced expiratory volume in the first second (FEV1; 0.0 L; 95% CI, −0.1 to 0.1 L), and no change in the rate of episodes of poor asthma control (relative risk [RR], 1.2; 95% CI, 0.9 – 1.5) or asthma-related quality of life (−0.1; 95% CI, −0.3 to 0.1). In addition, children treated with lansoprazole developed more respiratory infections (RR, 1.3; 95% CI, 1.1 – 1.6; P = .02) than those in the placebo group.

A subgroup of children in the study (n = 115) underwent esophageal pH studies before randomization; the prevalence of GER among this group was found to be 43%. In those children with a positive pH study, there was no positive treatment effect with lansoprazole vs placebo for any asthma outcome.

The most common adverse event reported among both groups was asthma exacerbation.

  • This is the exact opposite of what I would expect!

A higher prevalence of upper respiratory tract infections, sore throats, and episodes of bronchitis was noted among patients in the lansoprazole group. The study authors speculate that this may be a result of loss of host defense against bacterial colonization as a result of higher gastric pH levels.

“The results of this clinical trial are uniformly negative regarding the benefit of acid suppression therapy on symptom relief, lung function, airway reactivity, or quality of life,” write the authors. The results also “indicate that PPI therapy for poorly controlled asthma is not warranted.”

In an accompanying editorial, Fernando Martinez, MD, from the Arizona Respiratory Center, University of Arizona, Tucson, notes that although it is not a statistically significant difference, the increase in activity-related bone fractures in the lansoprazole group also raises concerns. This potential complication has prompted an advisory from the US Food and Drug Administration about the risk for fractures in adults receiving chronic PPI therapy.

Overall, however, Dr. Martinez praises the work of Dr. Holbrook and colleagues and concludes that “[g]iven their potential adverse effects, these medications should thus be used with great restraint for treatment of GER/[gastroesophageal reflux disease] during childhood. The substantial increase in use of PPIs in children during the last decade is worrisome and unwarranted.”

Support for this study was provided by the American Lung Association Asthma Clinical Research Centers Infrastructure Award and National Institutes of Health/National Heart, Lung, and Blood Institute grants. Dr. Holbrook and colleagues have disclosed no relevant financial relationships. Dr. Martinez has served as a consultant to MedImmune and has presented at an Abbott-sponsored seminar.

JAMA. 2012;307:373-381, 406-407.

Study Highlights

  • The Study of Acid Reflux in Children With Asthma was a randomized, masked, placebo-controlled, parallel clinical trial comparing lansoprazole vs placebo in children without overt GER but with poor asthma control despite treatment with inhaled corticosteroids.
  • Lung function measures, such as FEV1, asthma-related quality of life, and episodes of poor asthma control, were secondary endpoints.
  • In the subgroup with a positive pH study result, there was no apparent treatment effect for lansoprazole vs placebo for any asthma outcome, including asthma-related quality of life or lung function.
  • Lansoprazole was also ineffective in subgroups defined by markers of asthma severity (either FEV1 at baseline or oral corticosteroid use in the past year).
  • At least 1 serious adverse event occurred in 10 participants in the lansoprazole group and 9 in the placebo group.
  • Asthma exacerbation was the most common serious adverse event in both groups (15 of 25 reports).
  • The investigators concluded that in children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole did not reduce symptoms or improve lung function but was associated with increased adverse events.
  • The findings do not support routine esophageal pH testing to identify children who respond to PPIs, nor do they support trials of PPIs for poorly controlled asthma.
  • An accompanying editorial notes that the overuse of PPIs in childhood asthma is an example of “therapeutic creep,” or extending the use of a treatment with real or suggestive therapeutic effects in selected patients to other patients in whom the efficacy of that treatment has never been demonstrated.
  • The editorial also notes that therapeutic creep increases the risk for potential adverse effects without any added advantage for patients and may have significantly added to the marked increase in asthma drug costs.

Clinical Implications

  • Findings of a randomized, placebo-controlled trial suggest that PPI treatment of children with poorly controlled asthma but without symptomatic GER is not effective in reducing asthma symptoms or improving lung function.
  • In this randomized, placebo-controlled trial, the addition of lansoprazole was associated with increased adverse events, particularly respiratory tract infections. There may be significant safety concerns for long-term PPI use in children, meriting further research
  • I personally wonder if more aggressive use of Vitamin D replacement would be helpful for the increase in risk of fractures for the patients taking PPI medication.  Yes indeed, further research is warranted. 

Full reference on the dangers of PPI medications

Sleep disordered breathing

Often allergy patients have sleep disordered breathing and want to know if allergies contribute.  Most of the time, interruptions in your sleep due to allergy consist of congestion, snoring, sneezing, and possibly apnea.  Anything other than those symptoms should be evaluated for alternative causes.  Specialists dealing with sleep disorders are allergists, ENT (otolaryngologists) and pulmonologists.  There is a board-certification for sleep medicine, so you might want to check for this on listed credentials.  Good night! 

Sweet Dreams!

Sleep disordered breathing  (click to review slides; e-mail me if you need a password) —> lwiens@cox.net

Ouch! my tonsils are hurting me!

All that wheezes isn’t asthma!  Ever heard that before?  A common finding in our clinic is “wheezing” or difficulty breathing not due to asthma, but as a result of large tonsils/adenoids.  A typical history is as follows:

  • Snoring at night
  • He wheezes–(it’s not really wheezing, but loud noises coming from the lungs is often labeled as such)
  • I can never breathe through my nose
  • Examination reveals no wheezing in the chest, but coarse rhonchi transmitted to the chest from the upper airway
  • Look at these tonsils that are almost completely obstructing the back of the throat–

ENT doctors are the surgeons that perform T & A’s as they are popularly called.  (tonsillectomy/adenoidectomy)  The enthusiasm for removing tonsils in young children as a “routine” procedure as decreased because of intraoperative complications, but if it’s needed, the risks outweigh the benefits.  

Interesting patient of the day!

What would you think of a teenager seen for a rash, but come to find out he has swelling of hands and lips? Not to mention, other family members have similar problems! This may be hereditary angioedema, Type III. Why is this important? Treatment is available & it’s not steroids or anti-histamines. Check this out—>