Will early bacterial and viral exposure in urban inner city wheezing children be found to be caused by vastly different mechanisms compared to wheezing from bacterial infections in farming communities?

Answer:
There have not been any comparisons of viral exposure in farm children vs. inner city children. There was one paper that compared viral exposure in urban kids vs. suburban (Madison) kids, and the viral exposures, though not identical, were similar.¹

The new ECHO program (https://www.nih.gov/echo) due to begin this fall may help to provide answers about microbes and viruses in different settings. Most single center studies have local populations, making it hard to compare across different demographics. In ECHO, the goal is to enroll 50,000 children nationwide, which should facilitate comparisons of early life exposures (like viruses and bacteria) across different sites and populations. – James E. Gern, MD FAAAAI

Reference:
1. Gern JE, Pappas T, Visness CM, et al. Comparison of the Etiology of Viral Respiratory Illnesses in Inner-City and Suburban Infants. J Infect Dis. 2012;206(9):1342-9. doi: 10.1093/infdis/jis504

Reducing and/or Eliminating Asthma Exacerbations

Does a decrease in antiviral response seen in those with allergic asthma increase frequency and severity of upper respiratory infections?

Answer:
There has been considerable interest in the possibility that diminished antiviral responses, primarily a decreased production of interferons, is a risk factor for viral respiratory infections provoking asthma. Also, the decrease in antiviral responses enhances the possibility that a respiratory infection will provoke an asthma exacerbation. Many studies have found defective generation of type I and III interferons from isolated cells (infected by virus) from patients with asthma, i.e. respiratory epithelium, peripheral mononuclear cells, dendritic cells, and alveolar macrophages. These data suggest that patients with asthma, usually those with more severe disease, are more likely to have diminished antiviral responses and hence asthma exacerbations. The clinical extension and relevance of these observations have been seen in a number of studies including one in which nebulized interferon-β was given with a cold and reduced the frequency of an asthma exacerbation and the viral load;¹ the degree to which interferon-α generation from peripheral blood mononuclear cells is restored was associated with fewer exacerbations;² and finally, markers of defective interferon-β generation by alveolar macrophages are associated with a greater frequency of asthma exacerbations.³ Collectively, these data, both direct and indirect, support the relevance of defective antiviral activity in asthma as a risk for an exacerbation with viral respiratory infections. – William W. Busse, MD FAAAAI

References:
1. Djukanvoic R, Harrison T, Johnston SL, et al. The Effect of Inhaled IFN- β on Worsening of Asthma Symptoms Caused by Viral Infections. A Randomized Trial. Am J Respir Crit Care Med. 2014;190(2):145-54.
doi: 10.1164/rccm.201312-2235OC

2. Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136(6):1476-85.
doi: 10.1016/j.jaci.2015.09.008

3. Rupani H, Martinez-Nunez RT, Dennison P, et al. Toll-like Receptor 7 Is Reduced in Severe Asthma and Linked to an Altered MicroRNA Profile. Am J Respir Crit Care Med. 2016;194(1):26-37.
doi: 10.1164/rccm.201502-0280OC

 

What is the evidence that greater Eosinophil lowering results in greater clinical improvement in asthma?

Answer:
The data in clinical trials suggest that higher blood eosinophils or higher sputum eosinophils are associated with a greater risk of asthma exacerbations and worse clinical outcomes. Therapeutic agents that reduce eosinophils have been associated with clinical improvements. These include IL-5 blockers, CRTH2 antagonists, omalizumab and corticosteroids. – Thomas B. Casale, MD FAAAAI

References:
Muraro A, Lemanske RF Jr, Hellings PW, et al. Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2016;137(5):1347-58. doi: 10.1016/j.jaci.2016.03.010

Stokes JR, Casale TB. Characterization of asthma endotypes: implications for therapy. Ann Allergy Asthma Immunol. 2016;117(2):121-5. doi: 10.1016/j.anai.2016.05.016

 

Why limit the clinical benefit in the lower eosinophil range when studies have demonstrated efficacy reducing exacerbations?

Answer:
In a number of analyses looking at eosinophils as a biomarker for responsiveness to omalizumab, it appears that the reduction in exacerbation rates occurs almost exclusively in those patients with higher blood eosinophil levels. There are ongoing studies including PROSPERO that are attempting to better define predictors of responsiveness to omalizumab. – Thomas B. Casale, MD FAAAAI

Reference:
Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: An analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187(8):804-11. doi: 10.1164/rccm.201208-1414OC

 

Assuming equivalent safety profiles in a severe asthmatic with IgE of 350 and eosinophils of 600, would one pick one biologic over the other?

Answer:
Great question, and we have no direct answer. There have been no head-to-head trials comparing the effects of various biologics or good clinical trials determining if a failure of one biologic predicts a failure or success in another. I think it would be important to examine what one is trying to treat in regards to the patient’s profile. For example, if one is most concerned about exacerbations, then all of the biologics appear to have good effects in reducing exacerbations in patients with a blood eosinophil count of 600. However, even in patients with this high of a blood eosinophil level, the effects of omalizumab on FEV1 are very small, whereas the effects of IL-5 blockers and dupilumab are clinically and statistically significant. – Thomas B. Casale, MD FAAAAI

References:
Muraro A, Lemanske RF Jr, Hellings PW, et al. Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2016;137(5):1347-58. doi: 10.1016/j.jaci.2016.03.010

Stokes JR, Casale TB. Characterization of asthma endotypes: implications for therapy. Ann Allergy Asthma Immunol. 2016;117(2):121-5. doi: 10.1016/j.anai.2016.05.016

 

Is there is a difference between oral corticosteroids and parenteral administration in the management of exacerbations?

Answer:
The 2016 Update of the GINA Guidelines states the following concerning the management of Asthma Exacerbations:

Systemic corticosteroids

Systemic corticosteroids speed resolution of exacerbations and prevent relapse, and should be utilized in all but the mildest exacerbations in adults, adolescents and children 6–11 years.^367-369 (Evidence A). Where possible, systemic corticosteroids should be administered to the patient within 1 hour of presentation.^368,369 Use of systemic corticosteroids is particularly important in the emergency department if:

• Initial SABA treatment fails to achieve lasting improvement in symptoms

• The exacerbation developed while the patient was taking OCS

• The patient has a history of previous exacerbations requiring OCS

Route of delivery: oral administration is as effective as intravenous. The oral route is preferred because it is quicker, less invasive and less expensive.^370,371 For children, a liquid formulation is preferred to tablets. OCS require at least 4 hours to produce a clinical improvement. Intravenous corticosteroids can be administered when patients are too dyspneic to swallow; if the patient is vomiting; or when patients require non-invasive ventilation or intubation. In patients discharged from the emergency department, an intramuscular corticosteroid may be helpful,³⁷² especially if there are concerns about adherence with oral therapy.³⁷³

Dosage: daily doses of OCS equivalent to 50 mg prednisolone as a single morning dose, or 200 mg hydrocortisone in divided doses, are adequate for most patients (Evidence B). For children, an OCS dose of 1–2 mg/kg up to a maximum of 40 mg/day is adequate.³⁷⁴

Duration: 5- and 7-day courses in adults have been found to be as effective as 10- and 14-day courses respectively,^352,353 and a 3–5-day course in children is usually considered sufficient (Evidence B). Oral dexamethasone management of worsening asthma and exacerbations⁸³ for 2 days can also be used but there are concerns about metabolic side-effects if it is continued beyond 2 days.³⁷⁵ Evidence from studies in which all patients were taking maintenance ICS after discharge suggests that there is no benefit in tapering the dose of OCS, either in the short term³⁷⁶ or over several weeks³⁷⁷ (Evidence B).

367. Manser R, Reid D, Abramson M. Corticosteroids for acute severe asthma in hospitalised patients. Cochrane Database Syst Rev. 2000;2.

368. Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. Corticosteroids for preventing relapse following acute exacerbations of asthma. Cochrane Database Syst Rev. 2007:CD000195.

369. Edmonds ML, Milan SJ, Camargo CA, Jr., Pollack CV, Rowe BH. Early use of inhaled corticosteroids in the emergency department treatment of acute asthma. Cochrane Database Syst Rev. 2012;12:CD002308.

370. Ratto D, Alfaro C, Sipsey J, Glovsky MM, Sharma OP. Are intravenous corticosteroids required in status asthmaticus? JAMA. 1988;260(4):527-9. doi:10.1001/jama.1988.03410040099036

371. Harrison BD, Stokes TC, Hart GJ, Vaughan DA, Ali NJ, Robinson AA. Need for intravenous hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure. Lancet. 1986;1(8474):181-4. doi: 10.1016/S0140-6736(86)90654-9

372. Gries DM, Moffitt DR, Pulos E, Carter ER. A single dose of intramuscularly administered dexamethasone acetate is as effective as oral prednisone to treat asthma exacerbations in young children. J Pediatr. 2000;136:298-303. doi: 10.1067/mpd.2000.103353

373. Krishnan JA, Riekert KA, McCoy JV, et al. Corticosteroid use after hospital discharge among high-risk adults with asthma. Am J Respir Crit Care Med. 2004;170(12):1281-5. doi: 10.1164/rccm.200403-409OC

374. Kayani S, Shannon DC. Adverse behavioral effects of treatment for acute exacerbation of asthma in children: a comparison of two doses of oral steroids. Chest. 2002;122(2):624-8. doi: 10.1378/chest.122.2.624

352. Hasegawa T, Ishihara K, Takakura S, et al. Duration of Systemic Corticosteroids in the Treatment of Asthma Exacerbation; a Randomized Study. Intern Med. 2000;39(10):794-7. doi: 10.2169/internalmedicine.39.794

353. Jones AM, Munavvar M, Vail A, et al. Prospective, placebo-controlled trial of 5 vs 10 days of oral prednisolone in acute adult asthma. Respir Med. 2002;96(11):950-4. doi:10.1053/rmed.2002.1369

83. Sturdy PM, Victor CR, Anderson HR, et al. Psychological, social and health behaviour risk factors for deaths certified as asthma: a national case-control study. Thorax. 2002;57(12):1034-9. doi:10.1136/thorax.57.12.1034

375. Keeney GE, Gray MP, Morrison AK, et al. Dexamethasone for acute asthma exacerbations in children: a metaanalysis. Pediatrics. 2014;133(3):493-9. doi:10.1542/peds.2013-2273

376. O'Driscoll BR, Kalra S, Wilson M, Pickering CA, Carroll KB, Woodcock AA. Double-blind trial of steroid tapering in acute asthma. Lancet. 1993;341(8841):324-7. doi: 10.1016/0140-6736(93)90134-3

377. Lederle FA, Pluhar RE, Joseph AM, Niewoehner DE. Tapering of corticosteroid therapy following exacerbation of asthma. A randomized, double-blind, placebo-controlled trial. Arch Intern Med. 1987;147(12):2201-3. doi:10.1001/archinte.1987.00370120137023

That is, GINA and the available evidence suggest that oral delivery is as effective as IV (and presumably IM) for the treatment of acute asthma exacerbations.  However, some practitioners, including Dr Wendy Moore, who directs our Severe Asthma Clinic at Wake Forest, have found that some patients with severe asthma cannot be controlled with oral corticosteroids, but do appear to respond to IM steroids.  Hence, another difference between the art and science of medicine. – Stephen P. Peters, MD PhD FAAAAI

Reference:
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2016. Available from: www.ginasthma.org

 

If a type 2 asthma patient failed treatment with omalizumab, what is the chance the patient will respond to reslizumab or mepolizumab?

Answer:
Unknown. IgE and eosinophils, although somewhat related, are really different targets.   Many patients that have not responded to omalizumab have had dramatic reductions in their eosinophils with reslizumab or mepolizumab as opposed to what occurs with omalizumab. However, there are no data to show that patients with the same degree of blood eosinophilia respond better to IL- 5 blockers versus omalizumab. Furthermore, there are no controlled clinical trials showing that failures with anti-IgE respond to anti-IL-5 therapies. These are studies that need to be done. – Sally E. Wenzel, MD FAAAAI

Preventing and Treating Severe Asthma

How does removing some smooth muscle locally produce generalized beneficial effects? 

Answer:
The answer to this remains unknown. The beneficial effects may be due to myogenic or neurogenic effects that reverse proximal airway resistance. Our ability to discriminate upper and lower airway obstruction remains rudimentary. Bronchial thermoplasty (BT) will preferentially reverse upper airway obstruction. Recent studies suggest that BT may also modulate airway inflammation. To date, little is known concerning how BT improves asthma outcomes. – Reynold A. Panettieri, MD

Reference:
Panettieri RA Jr. Bronchial Thermoplasty: Targeting Structural Cells in Severe Persistent Asthma. Ann Am Thorac Soc. 2015;12(11):1593-4. doi: 10.1513/AnnalsATS.201509-627ED



Short of lung autopsies, what do you believe is the best test to evaluate nonsmokers with ACOS? Are lung compliance measurements (pressure/volume curves) or lung imaging (high resolution chest CT scans with parenchymal assessment [Voxels] useful?

Answer:
The question is important but unfortunately there is no definitive answer. ACOS usually implies the subject has/ had significant cigarette smoke exposure.  In the US, COPD is primarily caused by environmental smoke exposure.  Patients can develop irreversible airway obstruction in asthma. In that case, it is important to role out COPD by measuring the diffusion capacity and by following air trapping as measured by residual volume using body plethesmography.  Lung compliance measurements are not easily available to clinicians and are not a standard measurement.  Although CT imaging is intriguing in characterizing emphysema, the clinical value is uncertain in diagnosing COPD since COPD may manifest without emphysema and emphysema on CT scan doe not correlate with impaired lung function.
ACOS refers to patients that manifest some component of irreversible airway obstruction and some component of atopic/T2 inflammatory airway disease. One should rule out comorbid disease such as nasal polyps or GERD. I also suggest pre/post bronchodilator spirometry, serum IgE levels and eosinophil counts as well as skin testing or RAST. The rationale for these tests rests on a need to modify therapy. If there is a large pre/post BD difference then the addition of other bronchodilators maybe beneficial. If IgE and/or blood eosinophils are high then anti-IgE or - IL-5 therapy is warranted. – Reynold A. Panettieri, MD

Reference:
Postma DS, Rabe KF. The Asthma-COPD Overlap Syndrome. N Engl J Med. 2015;373(13):1241-9. doi: 10.1056/NEJMra1411863



Are DNAzymes organ specific?

Answer:
DNAzymes are antisense molecules which have two different properties: First, they have a DNA sequence which perfectly matches to a corresponding messenger RNA sequence (e.g. in the case of SB010 the DNAzyme has a DNA sequence matching the sequence of messenger RNA of GATA3). Second, they have an intrinsic catalytic domain which leads to the cleavage of the messenger RNA once the DNAzyme binds to the perfect target sequence.

Therefore, DNAzymes are highly specific therapeutic molecules which bind wherever they find the target. The target in this case (GATA3 mRNA) is expressed in T-cells, eosinophils, mast cells, and other cells involved in the regulation of the allergic inflammatory cascade.

In summary, DNAzymes are target-specific but not necessarily cell-, cell type-, or organ-specific. – Harald E. Renz, MD FAAAAI

Reference:
Potaczek DP, Garn H, Unger SD, Renz H. Antisense molecules: A new class of drugs. J Allergy Clin Immunol. 2016;137(5):1334-46. doi: 10.1016/j.jaci.2015.12.1344



In CAMP, ICS treatment prevented exacerbations but not loss in lung function. If exacerbations lead to loss of lung function, why did ICS therapy not protect lung function?

Answer:
That is an excellent question and the answer may be in the individual patient, the number of exacerbations suffered by that patient, as well as the type of virus and the severity of the illness. This combination may override the beneficial effect of ICS on reducing, but not preventing exacerbations. For additional information, you might read the recent CAMP publication by McGeachie et al, N England J Med 2016;374:1842–52 that describes the varying patterns of lung growth that emerge from children with asthma. Of interest, there are groups of patients with reduced lung function that are associated with a higher number of exacerbations as well as an increased medication requirement. – Stanley J. Szefler, MD FAAAAI

Reference:
McGeachie MJ, Yates KP, Xiaobo Z, et al. Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma. N Engl J Med. 2016;374:1842-1852.
doi: 10.1056/NEJMoa1513737

Asthma and COPD Overlap Syndrome (ACOS)

Short of lung autopsies what do you believe is the best test to evaluate nonsmokers with ACOS?

Answer:
Excellent question. Beginning around 2000, I published several articles all documenting the loss of lung elastic recoil in well treated, never smoked, chronic asthmatics with persistent expiratory airflow limitation, yet normal diffusing capacity. High resolution, thin section lung CT demonstrated at best, mild areas of lung tissue breakdown in upper lung fields. While I suspected emphysema, I had to prove it. Starting in 2004, I obtained autopsies when these asthmatics died and in all 5 cases they all had centrilobular emphysema in air/formalin inflated lung specimens. Most physicians don`t understand this epiphenomenon. Please go to www.pubmed.gov and search gelb af and my refs 1, 2, 3, and 5 will be very helpful. – Arthur F. Gelb, MD

References:
Gelb AF, Christenson SA, Nadel JA. Understanding the pathophysiology of the asthma-chronic obstructive pulmonary disease overlap syndrome. Curr Opin Pulm Med. 2016;22(2):100-5. doi: 10.1097/MCP.0000000000000236

Gelb AF, Nadel JA. Understanding the pathophysiology of the asthma-chronic obstructive pulmonary disease overlap syndrome. J Allergy Clin Immunol. 2015;136(3):553-5. doi: 10.1016/j.jaci.2015.06.013

Gelb AF, Yamamoto A, Mauad T, Kollin J, Schein MJ, Nadel JA. Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction. J Allergy Clin Immunol. 2014;133(1):263-5.e1-3. doi: 10.1016/j.jaci.2013.09.045 Erratum in: J Allergy Clin Immunol. 2014;133(4):1232 doi: 10.1016/j.jaci.2014.02.003

Gelb AF, Yamamoto A, Verbeken EK, Nadel JA. Unraveling the Pathophysiology of the Asthma-COPD Overlap Syndrome: Unsuspected Mild Centrilobular Emphysema Is Responsible for Loss of Lung Elastic Recoil in Never Smokers With Asthma With Persistent Expiratory Airflow Limitation. Chest. 2015;148(2):313-20. doi: 10.1378/chest.14-2483