Q:

7/9/2013
I recently saw a 33 year-old male with severe persistent asthma with an allergic component, perennial allergic rhinitis (with springtime allergic conjunctivitis), and AERD. At the first visit, he had been recently discharged from ICU after intubation for asthma, the sixth intubation in the eight years since asthma diagnosis. Asthma is triggered by pollens and aspirin, and is worse in the winter (possibly due to dust mite allergy as listed below).

The second visit, two weeks later, his nasal polyposis was increasingly symptomatic, with large bilateral polyps and increased sinus pressure. Symptoms responded to Prednisone and antibiotics (he felt better when I called to follow up after 1 week). He is maintained on Symbicort, Singulair, and Spiriva (prescribed by pulmonologist), and Prednisone tapers when needed. He was using Symbicort 80/4.5 mcg two puffs once daily when he last got hospitalized. I increased this to 160/4.5 mcg two puffs twice daily.
FEV1 was 75% predicted.

Total IgE was 144 IU/mL, and IgE to D. pter was 4.12 kU/L, D. farinae 4.32 kU/L,and Kentucky Bluegrass 0.13 kU/L.

There was no eosinophilia on recent CBC (performed off of Prednisone).

My question regards further treatment approach/timing- I would like to treat him with Omalizumab first. I think he may also benefit from aspirin desensitization for the AERD component. My inclination would be to start with Xolair to hopefully control the asthma better, and then refer him to an academic center for the aspirin desensitization. At some point, assuming asthma control is achieved, I would hope to offer immunotherapy. Would this be the order in which you would approach this?

A:

Thank you for your inquiry.

I do agree with the addition of omalizumab and the consideration of aspirin desensitization. I would also consider adding beclomethasone HFA to the treatment regimen since we know that small airway obstruction can contribute to exacerbations. In addition, I would also consider switching his montelukast to zileuton. However, because of his expertise and some very exciting recent advances in the area of aspirin-exacerbated respiratory tract disease, as well as his extensive clinical experience in patients such as the one you described, I am asking Dr. Larry Borish for his input on potential treatment strategies in your patient, especially in regards to the suggestion regarding the switch from montelukast to zileuton. As soon as we receive Dr. Borish’s response, we will forward it to you.

Thank you again for your inquiry.

Sincerely,
Phil Lieberman, M.D.

We have received a response from Dr. Larry. Thank you again for your inquiry and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

Response from Dr. Larry Borish:
On my 1st reading of this case I assumed this was a straightforward question about severe asthma in someone with AERD. On further reading I think this is much more a case where the whole diagnosis of asthma is worthy of being questioned. Between the 6 intubations and the no eosinophils I'm not sure what this really is with the info given. So, half this paper has become a discussion on the importance of questioning diagnoses including asthma, nasal polyps, aspirin allergy, etc. And then briefly we delve into the AERD comments. But I wouldn't give this patient xolair let alone aspirin desensitization without being a lot more convinced that he has asthma, polyps, etc., etc.

Hope you are happy with this approach!

Larry Borish, M.D.
 
Detailed response from Dr. Larry Borish:
When dealing with a particularly severe asthmatic - and there is nothing more compellingly severe than someone requiring intubation on 6 separate occasions who was clearly not responding to whatever therapeutics were being provided at the time of those intubations - the first consideration has to be certainty of the diagnosis. Asthma is itself a collection of heterogeneous diseases that can also masquerade as a multitude of other diagnoses. Obesity, vocal cord dysfunction, dysfunctional breathlessness, severe reflux with aspiration, COPD, congestive heart failure, any many more conditions can all mimic the presentation of asthma, leading to the quagmire that we know as "asthma" today1. The patient in this vignette is on medium dose inhaled corticosteroids for a presumed diagnosis of asthma and with laboratory evidence of sensitization to allergens. There is a history of reported allergy to aspirin and, on physical exam, nasal polyps were observed. On the surface, the may seem to be a straightforward presentation of Aspirin Exacerbated Respiratory Disease (AERD). However, before delving into a discussion of the management of AERD, it seems that each facet of this presentation needs to be scrupulously reconsidered. Especially before considering expensive life-long interventions that might not be helpful, the initial approach to this - or any - patient with severe, potentially life-threatening, and seemingly steroid resistant asthma must include a thorough examination of the data and further testing to confirm the diagnosis.
 
In the patient above, the limited history can provide some important clues as to the diagnosis.  Simply knowing that the patient has been intubated 6 times in 8 years gives the clinician instant trepidation. In uncomplicated asthma, this is a rather unusual history. Amongst conditions that masquerade as asthma, it is patients with vocal cord dysfunction who are much more regularly intubated - because of the apparent severity of their presentations2. A quick survey of our own experience includes many physicians and EMT's who have intubated patients who "look like they will tire out soon." However, few of these patients have objective evidence of tiring. At the very least this should include arterial blood evaluation as, for truly asthmatic patients requiring intubation, this would uncover an elevated (or rising pCO2) and - in contrast to VCD - an elevated Arterial-alveolar pO2 gradient. Further investigation into hospital ventilator records would reveal the high lung pressures and low lung volumes defining the poor pulmonary compliance of asthma, in contrast to the normal compliance seen in VCD.
 
For this patient, the only information we have supporting the diagnosis of obstructive lung disease is a slightly low FEV1. However, isolated, the significance of this finding is unclear. Of course, the diagnosis of obstruction cannot be entertained without information regarding FVC and repeat spirometry after bronchodilator will address the question of reversibility. It is important to remember that everything with a low FEV1 is not asthma, as numerous considerations including poor technique, obesity, COPD, and numerous others can consistently mimic this finding. Ultimately, the gold standard for diagnosis of asthma remains the methacholine challenge. In the absence of compelling information not provided in this brief vignette, arguably all patients with seemingly severe, steroid-resistant asthma and with an FEV1 > 70% who have these sorts of inconsistencies in their presentation should undergo a methacholine challenge.

The reported presence in this patient of nasal polyposis (NP) does seem supportive of the diagnosis of asthma, something present in many if not most NP patients. It should be noted how this diagnosis was made as on anterior rhinoscopy many anatomical variants (e.g., a deviated septum with a readily visualizable middle turbinate) are often misconstrued to be a NP. Typically this diagnosis is best made via rhinoscopy although significant hyperplastic disease observed on a sinus CT can strongly support the diagnosis of NP (and - when present - the likelihood of concomitant asthma3.

Once confirming the diagnosis of CRSwNP and asthma, it is the reported history of "sensitivity" to aspirin that suggests AERD - Samter's triad. However, like everything else in the realm of severe asthma, the diagnosis of AERD can be difficult. This diagnosis is best supported by a compelling history of upper and/or lower respiratory compromise in response to aspirin (or other NSAID) occurring on two separate occasions4. Again, this history can be deceiving, as many people who consider themselves allergic to aspirin are simply describing the natural circadian history of their asthma. And, alternatively, ASA/NSAID-induced exacerbations of GERD may trigger upper and lower airways symptoms in the absence of AERD. Importantly, a history of urticaria/angioedema after taking aspirin is emphatically not associated with the diagnosis of AERD, and these patients should be diagnosed and treated differently. Unambiguous confirmation of aspirin allergy is nearly impossible in the absence of direct aspirin challenge, as it is not IgE mediated, and, therefore, there are no skin or blood tests that are diagnostic. Recent studies suggest that a nasal ketorolac challenge is effective at determining who is allergic to aspirin5.

There is one striking finding in this vignette that most places in doubt the diagnosis of AERD (if not asthma) and that is the absence of eosinophilia at a time when the patient was not on corticosteroids. Peripheral eosinophilia is a cardinal feature of AERD, and a patient without this lab finding almost certainly does not have this disease6, 7. It is certainly possible to have asthma without peripheral (or for that matter airway) eosinophilia however this is not seen in AERD.  

AERD patients have particularly severe CRS sinus CT will reveal severe, nearly opacified sinuses upon CT 8. It is also interesting that this patient was atopic. Allergy is not a feature of AERD9, 10, 11 and when present this is likely just the concomitant presence of an unrelated but common phenotype.

For a patient (probably not the one in this vignette) who does have AERD, after the presence of polyps is confirmed by CT scan or rhinoscopy, a "medical polypectomy," is the initial approach. A "medical polypectomy" is defined as a steroid taper over ~21 days.  This will only provide transient relief but after shrinking the polyps and hopefully reopening the sinus ostia, saline rinses with the addition of a topical corticosteroid such as budesonide can be started12. Generally, repeat rhinoscopy after the "medical polypectomy" can be useful to determine if the treatment was successful. If this is not effective, surgical intervention is required. Patients with AERD are occasionally helped by leukotriene receptor antagonists but for yet unclear reasons these patients may be uniquely responsive to the 5-lipoxygenase inhibitor, zileuton13. As a single intervention in AERD, this agent can shrink polyps, improve sinus symptoms, markedly improve asthma, and - in over half the patients - restore sense of smell. If these approaches fail, the next consideration would be aspirin desensitization4, 14. We prefer to do this shortly after surgery (within four weeks) both because aspirin desensitization seems to work better to prevent regrowth of polyps than to eliminate established disease and it is also our experience that removal of the sinus tissue mitigates the volume of leukotrienes produced during the desensitization and makes for a safer procedure. Aggressive medical management must be continued after surgery and aspirin desensitization, likely including zileuton and topical corticosteroid-containing saline nasal rinses, to retard the growth of polyps.   

For the concerns discussed, the use of omalizumab in this patient is debatable, and it would require many of the tests delineated above to determine its appropriateness. If this patient truly has allergen-exacerbated asthma (with or without concomitant AERD) then, in the presence of his dust mite allergy, omalizumab might decrease future exacerbations and hospitalizations. But again, our first approach for this patient is to rule out a masquerading diagnosis such as obesity, vocal cord dysfunction, COPD, etc. and subsequently, to focus on a treatment plan unique for AERD - if that is similarly confirmed - as in our experience IgE sensitivities have modest impact in that condition.  Finally, the use of antibiotics for this patient's chronic sinusitis is also controversial, and recent studies suggest that antibiotics may actually be detrimental in many patients15, 16.  

Larry Borish, MD                        
Professor of Medicine
University of Virginia Health Systems    
Charlottesville, VA                      

Joshua Kennedy, MD
Assistant Professor of Pediatrics
University of Arkansas Medical Sciences
Little Rock, AR

References:
1. Le AV, Simon RA. The Difficult-to-Control Asthmatic: A Systematic Approach. Allergy, Asthma, and Clinical Immunology: official journal of the Canadian Society of Allergy and Clinical Immunology 2006; 2:109-16.

2. Newman KB, Mason UG, 3rd, Schmaling KB. Clinical features of vocal cord dysfunction. American Journal of Respiratory and Critical Care Medicine 1995; 152:1382-6.

3. Newman LJ, Platts-Mills TA, Phillips CD, Hazen KC, Gross CW. Chronic sinusitis. Relationship of computed tomographic findings to allergy, asthma, and eosinophilia. JAMA : the Journal of the American Medical Association 1994; 271:363-7.

4. Macy E, Bernstein JA, Castells MC, Gawchik SM, Lee TH, Settipane RA, et al. Aspirin challenge and desensitization for aspirin-exacerbated respiratory disease: a practice paper. Annals of Allergy, Asthma & Immunology: official publication of the American College of Allergy, Asthma, & Immunology 2007; 98:172-174.

5. Lee RU, White AA, Ding D, Dursun AB, Woessner KM, Simon RA, et al. Use of intranasal ketorolac and modified oral aspirin challenge for desensitization of aspirin-exacerbated respiratory disease. Annals of Allergy, Asthma & Immunology: official publication of the American College of Allergy, Asthma, & Immunology 2010; 105:130-5.

6. Payne SC, Borish L, Steinke JW. Genetics and phenotyping in chronic sinusitis. The Journal of Allergy and Clinical Immunology 2011; 128:710-20; quiz 21-2.

7. Sampson AP, Cowburn AS, Sladek K, Adamek L, Nizankowska E, Szczeklik A, et al. Profound overexpression of leukotriene C4 synthase in bronchial biopsies from aspirin-intolerant asthmatic patients. International Archives of Allergy and Immunology 1997; 113:355-7.

8. Mascia K, Haselkorn T, Deniz YM, Miller DP, Bleecker ER, Borish L. Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. The Journal of Allergy and Clinical Immunology 2005; 116:970-5.

9. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. The Journal of Allergy and Clinical Immunology 2003; 111:913-21; quiz 22.

10. Sanak M, Szczeklik A. Genetics of aspirin induced asthma. Thorax 2000; 55 Suppl 2:S45-7.

11. Szczeklik A, Nizankowska E. Clinical features and diagnosis of aspirin induced asthma. Thorax 2000; 55 Suppl 2:S42-4.

12. Steinke JW, Payne SC, Tessier ME, Borish LO, Han JK, Borish LC. Pilot study of budesonide inhalant suspension irrigations for chronic eosinophilic sinusitis. The Journal of Allergy and Clinical Immunology 2009; 124:1352-4 e7.

13. Dahlen B, Nizankowska E, Szczeklik A, Zetterstrom O, Bochenek G, Kumlin M, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. American Journal of Respiratory and Critical Care Medicine 1998; 157:1187-94.

14. Stevenson DD, Hankammer MA, Mathison DA, Christiansen SC, Simon RA. Aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma: long-term outcomes. The Journal of Allergy and Clinical Immunology 1996; 98:751-8.

15. Abreu NA, Nagalingam NA, Song Y, Roediger FC, Pletcher SD, Goldberg AN, et al. Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis. Science Translational Medicine 2012; 4:151ra24.

16. Kennedy JL BL. Chronic Rhinosinusitis and Antibiotics:  The Good, the Bad, and the Ugly. American Journal of Rhinology and Allergy 2013; Pending publication.

AAAAI - American Academy of Allergy Asthma & Immunology