Clinical Guidelines: Report on Asthma Guideline Term Paper

The clinical guideline and associated recommendations

Asthma is a chronic inflammatory disorder of the airways with airway hyper-responsiveness. The aim of this term paper is to assess the latest report on asthma guidelines (EPR-3) (Busse et al., 2007). The guideline illustrates diagnostic procedures for assessment of severity and control of asthma based on presence of airway hypersensitiveness, reversibility of airflow, detailed medical history, respiratory tract, skin and chest examinations, spirometry to assess obstruction, and exclusion of other chronic pulmonary obstructive diseases.

Forced expiratory volume to forced vital capacity ratios (FEV/FVC), by spirometry, was recommended as the main criterion to assess severity. Periodic monitoring (signs and symptoms, FEV/FVC, and peak flow measurements, asthma exacerbations’ history, etc.), and referral to a specialist in extreme severity were also recommended. Education through the written asthma action plan of handling metered-dose inhalers, smoking avoidance, household environmental consciousness (indoor and outdoor allergens, mites, cockroaches, etc.), and clinical guidance was emphasized.

Avoidance of non-specific beta₂ blockers and aspirin, sulfite-containing and other food, occupational pollutants, single and multiple allergen immunotherapy, and tests for sensitivity to non-steroidal anti-inflammatory drugs, sinusitis, and nasal polyps were also recommended. Chronic comorbid conditions like obesity, rhinitis/sinusitis, chronic stress/depression, gastroesophageal reflux disease, obstructive sleep apnea were related to asthma severity.

Recommendations for medications for long-term control were: inhaling corticosteroids, cromolyn sodium, nedocromolin, immunomodulators, leukotriene modulators, bronchodialators, methylxanthines, and short term quick relief were: anticholinergics, strong bronchodialators, systemic corticosteroids etc. It was recommended that use of immunomodulators inhalations may have potential risk. In adults, health problems associated with prolong treatment were listed, and possible remedy measures were formulated. Adjunctive drugs (omalijumab) were recommended in severe untreatable cases only. Other specialized drugs recommended to be within recommended doses were leukrotriene receptor antagonists (fluticasone), lipoxygenase inhibitors (Zileuton) and beta₂ agonists.

Indicate the group who developed the guidelines on the particular topic

The recommendations were delivered by National Asthma Education and Prevention Program (NAEPP) coordination committee. An expert panel was set up by the National Heart, Lung, and Blood Institute (NHLBI) to update the asthma guidelines. It is an update from previous published report by same agency (EPR-2 Update; Murphy et al., 2002).

The committee comprised experts from University of Wisconsin Medical School Madison, University of California–San Francisco, Massachusetts General Hospital, Columbia University, Advocate Health Center, Chicago, University of New Mexico Health Sciences Center, Albuquerque, University of Wisconsin Hospital and Clinics, University of Arizona Medical Center, U.S. Food and Drug Administration, National Jewish Medical and Research Center, University of Virginia School of Medicine, University of Washington, University of Nevada School of Medicine, Brigham & Women’s Hospital, and Olmstead Medical Center.

Indicate whether the guidelines are evidence based or not

Based on numerous asthma related research articles, evidence tables were prepared. These evidences were generated from tabulating the abundance of cases of a particular type and these were then categorized as:

1. randomized trials with consistent findings,
2. limited yet positive evidence after statistical analysis,
3. nonrandomized uncontrolled trials and further less consistent data,
4. to selected observations deemed to be important by the panel members.

The strength of recommendations was also graded on a ranking system, based above category of observations and interpretations. Normally, the evidence category A was highly emphasized, and D was not recommended or with caution.

Assess the validity of the guideline

The guidelines were based on factual observations from peer-reviewed journal, and wherever doubts existed, were clarified. Urbano (2008), based on recommendation of nine asthma experts, came up with all-positive validation report. Seven key educational messages were extracted,

1. accurate diagnosis,
2. comprehensive management,
3. monitoring control,
4. step-wise initial and follow-up therapy,
5. special situation management, and
6. managing exacerbations.

Loschen (2008) attempted to practically apply the guideline for patient care. In limited samples tested, the patients were not controlled as per guidelines, and a change in therapy was required. Considering this anomaly in evidence- and trial-based recommendations, Bousquet et al. (2006) emphasized for a true global guideline, considering varied socio-economic conditions and racial/ethnic groups.

This is because asthma is diagnosed late in low-income communities, who can not afford inhaled corticosteroids and visits to specialists (Ait-Khaled et al. 2006). Though genetic lineage of asthma prevalence is not proven in ethnic communities, it can be another factor (Ghosh et al., 2003). Smith et al. (2005) found that non-Hispanic black children were more affected by asthma than American Whites. There are also country-specific asthma guidelines (Rai et al., 2007), and for validation, such evidence-based regional guidelines need to be considered and their specific recommendations to be incorporated.

Use the agree instrument

The agree instrument (Cluzeau & Burger, 2001) is used with ranking in parenthesis and comments:

1. The overall objectives of the guideline are specifically described [4]: Due to recent innovation in asthma-related medication, an update was necessitated. Five objectives were identified:
   1. Establishing accurate diagnosis system to evaluate asthma severity,
   2. Initial step-wise approach of therapy depending on severity,
   3. Assessing environmental factors affecting asthma control,
   4. Educating patients, family and the physicians to control asthma,
   5. Establishing pharmacologic therapy for asthma and exacerbations, which includes written asthma action plan, and
   6. Managing special situations. The asthma action plans, special education, and diagnostic and therapeutic innovations were novel components, not considered earlier.
2. The critical questions covered by the guideline are specifically described [4]: The questions as to how effective is spirometry in accurate diagnosis, does reversibility on spirometry demonstrate reversibility of signs and symptoms, how to avoid misdiagnosis of other pulmonary conditions, how to maintain written asthma plan, what should be the course of pharmacologic therapy, the doses of inhaled corticosteroids (ICS), long acting beta2 agonists (LABA), leukotriene modifiers (LM) and the new immuno-modulators (omalizumab), and the risks associated with such therapy, what is the step-wise approach for initial and ongoing therapy like short-acting bronchodialators, LABA LM and omalizumab etc, and in case of severe life threatening exacerbations, how to switch to other therapy like of short acting beta2 agonists (SABA), oxygenation etc., have been elaborately described, discussed and explained.
3. The patients to whom the guideline is meant to apply are specifically described [3]: Age is an important consideration, and besides adults, children of < 5, 5-12, and > 12 age groups were segregated. Accordingly, treatment strategies were formulated. In the step-wise approach, only low dose of ICS and no adjunctive therapy was recommended for 1 – 4 year. For older children, medium dose ICS was combined with low dose low dose LABA, and for > 12, addition of omalizumab was considered. Pharmacologic treatments were also age specific, and in children recommendation was for only minimum therapy, and if required step-down therapy. Asthma intermittent groups were to be treated by SABA, while persistent groups were to be treated initially with ICS followed by step-wise medication. For managing special situations like exercise-induced bronchospasm, surgery, pregnancy, and racial and ethnic groups, the treatment strategies included intranasal corticosteroids and SABA.
4. The guideline development group includes individuals from all the relevant groups [4]: NAEPP coordination committee comprised of experts like healthcare research professionals, experts from allergy and asthma network and academies, pharmacists, clinical environmentalists, epidemiologists, food and drug controllers, family physicians, pediatricians, and doctors from chest, respiratory and lung associations. The EPR-3 was constituted by experts who served as officials or were consultants for leading companies like GlaxoSmithKline, Merck, Novartis, Pfizer, Centocor, Dynavax, Genentech/Novartis, Isis, Schering, Atlanta, Wyeth etc. There was a 12 member panel of reviewers from reputed medical centers who reviewed the draft before publication.
5. The patients’ views and preferences were sought [2]: The recommendations were based on medical papers, in which patients’ comments might have been incorporated. EPR-3 refers to the data of Gaining Optimal Asthma Control (GOAL) randomized double-blind study, which involved 3,421 patients with intermittent asthma, who were treated with fluticasone propionate and salmeterol/fluticasone with lower incidences of exacerbations and better life-style. The FEV1/FVC data were gathered from patients at National Health and Nutrition Examination Survey, National Center for Health Statistics and Centers for Disease Control and Prevention, for diagnosis recommendations.
6. The target users of the guidelines clearly identified [2]: The guideline was not targeted to any specialist clinician, but was directed to patients and family/community members and environmentalists. Apparently, the primary targets are the pharmaceutical companies manufacturing the asthma drugs. Indirectly, the professionals in research and development sector were benefited with vast information on generic drugs, which are still under trials for asthma and can be directly applied for patient care.
7. The guidelines have been piloted among target users [3]: As indicated, pilot study was done by GOAL. Another randomized placebo-controlled trial of salmeterol vs. placebo was included for adults to assess its safety. The outcomes of the study revealed concern of using LABA as sole drug in prolong therapy. Later, FDA warned about the side effects of such treatments and LABA was prescribed in conjunction with long-term ICS treatment.
8. Systematic methods were used to search for evidence [4]: The panel members searched for peer reviewed medical journals in MEDLINE database. To organize the review process the panel was divided in 10 committees with lead teams, who were responsible for topics like, assessment and monitoring, patient and provider education, control of causative factors, pharmacologic therapy (ICS, LM, and bronchodialators), special alternative medication, and managing exacerbations. About 15,444 titles were searched, of which 4,747 were short-listed, 2,800 abstracts were retrieved based on relevance and quality, from which 2,122 full text articles were reviewed and from this 1,654 were finally used for referencing.
9. The criteria for selecting the evidence are clearly described [4]: A total of 20 evidence tables were prepared from 316 articles. Evidence category 1 was based on randomized controlled trials-rich body data, which means consistent pattern of findings for a particular population. Evidence category 2 included only the limited evidence of patients, and was subjected to post hoc and statistical treatments, and Meta analysis. The interpreted data were less significant, though highly consistent. In evidence category 3, observations from nonrandomized uncontrolled trials were kept, and evidence category 4 included selected observations deemed to be important by the panel members. The strength of recommendations was also graded on a ranking system, based above category of observations and interpretations. For e.g. long-term corticosteroid and cromolyn treatments, and beta2 agonists as short-term treatment was recommended as Evidence A. Immuno-modulators were, however, recommended as Evidence B for age >12 year, which means data are not strong enough to unequivocally recommend. Dose dependence and drug delivery system had even less consistency and was recommended as Evidence C.
10. The methods used for formulating the recommendations are clearly described [4]: After preparing the evidence tables, the respective members adopted an iterative process of interpreting the evidences and drafted initial report after incorporating reviewers’ comments. All such drafts were compiled and after a panel discussion with full consensus the final guideline was drafted.
11. The health benefits, side effects, and risks have been considered while formulating the recommendations [4]: As many new drug formulations and therapy choices were prescribed, there were discussions held on their merits/demerits. Health benefit of spirometry was highly emphasized. Equal weight was given to increase doses of ICS and LABA and on adding immunodialating therapy with omalizumab, for persistent and severe asthma. The risk components were also highlighted in asthma action plan, such as likelihood of exacerbations, progressive decline in lung function (reduced lung growth in children), risks of side effects of medication etc. Use of omalizumab was recommended with reservations, because of its anaphylactic action. LABA associated asthma related life-threatening risks were cautioned. It was cautioned that children < 5 can be misdiagnosed for asthma and treatments that too only with ICS have to be very carefully evaluated before applying.
12. There is an explicit link between the recommendations and the supporting evidence? [3]: Every recommendation was supported by references from which the evidence tables were made, regardless of whether the evidences support or oppose the nature of particular therapy. As the evidences were ranked, they were linked to the recommendations at every stage.
13. The guidelines have been externally reviewed by experts prior to publication [3]: The guidelines were also externally reviewed by a panel of consultant reviewers comprising 14 experts in the field of asthma and pulmonary diseases. Besides, the NHLBI staff (5 members) and American Institute for Research Staff (4 members) were also instrumental in preparation of guidelines. Many other professional societies, voluntary health and consumer/patients advocacy organizations and industry were also consulted during public review of the guideline.
14. A procedure for updating the guidelines provided [3]: As this is already an updated guideline of EPR-update (Murphy et al., 2002), not much systematic procedure has been laid to suggest mechanisms to further update it. There were lacuna in the previous guidelines mostly because the information were either not available or were misleading, and these were rectified. However, updating guidelines is sought for children > 5 year and for special cases like exercise, surgery, pregnancy, other pulmonary diseases etc.
15. The recommendations are specific and unambiguous [4]: As the evidence tables were ranked, there was clear difference between certainty and uncertainty of the management. Precise description of management was given at every level, from diagnosis, initial therapy, and follow-up pharmacological and environmental control. Every procedure was elaborately described without any ambiguity. Further, the recommendations were spelled in charts, pictures, tables and figures, enabling easy understanding of the procedures. For example, step-wise improvement of therapy was explained in point-wise manner in algorithm with respect to every drug included in the therapy, their health effects, dose, duration of application and risk factors.
16. The different options for management of the condition are clearly presented [4]: Different options for medication were considered. For e.g. in step-wise therapy the following medication was recommended: step 1 includes SABA, step 2 gives preferred low dose ICS or alternatively low dose LM drugs, step 3 gives low dose ICS + LABA or medium dose ICS or low dose ICS + LM drugs, step 4 gives medium ICS + LABA or medium ICS + LM, and steps 5-6 give high dose ICS + LABA or omalizumab.
17. Key recommendations are clearly identifiable [4]: Recommendations were presented in boxes and figures at the end of the section. The figures include charts, questionnaire, pictures and algorithms Step-wise treatment was very well depicted in a seven bar algorithm. Asthma management section had 4 boxes and 34 figures, Long term asthma management section had 1 box and 15 figures, and Managing exacerbations of asthma section had 10 figures.
18. The guideline supported with tools of application [3]: Introductory sections preceded each detailed sections. Key points gave an overview summary of each section followed by the key differences from the previous guidelines. At the end of each section many references were provided to support the contents given in the section. This means that the previous guidelines were taken as baseline tools, and all improvements were thoroughly depicted in the current document.
19. The potential organizing barriers applying the recommendations have been discussed [4]: Although many panel members independently searched references, short-listed the relevant texts and made their own sets of evidence tables, their interests never clashed and in the panel discussions they could arrive to a common set of guidelines. No organizational, bureaucratic or even procedural problems were associated with this report, as mentioned.
20. The potential cost implications of applying the recommendations have been considered [2]: This aspect is completely missing. The cost of diagnosis, treatment and management of asthma and environmental clean-up costs should have been assessed. Most of the immunomodulators, leukotriene modulators, bronchodialators etc. must be expensive and regular use may lead to side effects, which has to be treated by experts, involving cost. In special cases like life-threatening exacerbations, surgery, pregnancy etc. the cost becomes a critical issue; did not fine any space in the report.
21. The guideline presents key review criteria for monitoring and/or audit purpose [3]: Asthma diagnosis to evaluate severity of the symptoms decides the follow-up treatment strategy. In this guideline, the review to evaluate the severity during diagnosis is well documented. For e.g. frequency of severe or recurrent episodes of coughing, wheezing, chest tightness, night awakening, pre- and post bronchodialator, FEV/FVC, etc. are criteria to review the patient’s conditions for determining the step-up therapy. The complete medical history has been considered as another instrument to evaluate the nature of allergy, which should be tested before suggesting course of treatment.
22. The guideline is editorially independent from the funding body [4]: NHBLI partially supported the members while most funding was done for the independent sources not related to this work, or they volunteered. The EPR members received independent funding for travel etc., as they disclosed, from pharmaceutical companies, they are associated with. Thus editorially it was independent fro funding bodies.
23. Conflicts of interest of guideline development members have been recorded [4]: On record, there is no conflict among the panel members as they worked independently gathering information and prepared their evidence tables. Subsequently, they prepared initial document with consensus and sought help of external agencies for reviewing.

Further comments

It appears that there was a bias towards drug manufacturers and pharmaceutical companies, who probably would be most benefited as the complete set of new medication was introduced. Another important feature is rehabilitation of the patients by educating them to cope with asthma health- and environment related problems.

Overall recommendations: [Strongly recommended]

The given guideline is the most updated and most comprehensive document for asthma diagnosis, management and cure. Novel drugs were prescribed with their doses and courses, which certainly would benefit society at large. The rehabilitation strategy and pharmaceutical therapy will have long term implication in patient care.

References

Aït-Khaled, N., Enarson, D.A., Bencharif, N., Boulahdib, F., Camara, L.M., Dagli, E., et al. (2006). Implementation of asthma guidelines in health centres of several developing countries. International Journal of Tuberculosis and Lung Diseases, 10(1), 104-109.

Bousquet, J. Godard, P. & Grouse, L.(2006).Global integrated guidelines are needed for Respiratory diseases. Primary Care Respiratory Journal, 15, 10-12.

Busse, W.W., Boushey, H.A., Foggs, M.B., Janson, S.L., Kelly, W.H., Lemanske, R.F., Martinez, F.D., et al.(2007). EPR-2007-Expert panel report: guidelines for the diagnosis and management of asthma. Update on selected topics. Bethesda, NIH Publication No. 07-4051.

Cluzeau, F. & Burger, J. (2001). Appraisal of guidelines for research & evaluation AGREE) – Appraisal instrument. Web.

Ghosh, B., Sharma, S. & Nagarkatti, R. (2003). Genetics of asthma: current research paving the way for development of personalized drugs. Indian Journal of Medical Research, 117, 185-197.

Loschen, J. (2008). New asthma guidelines: how will they affect patient care? Web.

Murphy, S., Bleecker, E.R., Boushey, H.A., Buist, A.S., Busse, W.W., Clark, N.M., et al. (2002). EPR-2 Update-Expert panel report: guidelines for the diagnosis and management of asthma. Update on selected topics. Bethesda, NIH Publication No. 02-5074.

Rai, S.P., Patil, A.P., Vardhan, V., Marwah, V., Pethe, M. & Pandey, I.M. (2007). Best treatment guidelines for bronchial asthma. Medical Journal of Armed Forces India, 63, 264-268.

Smith, L.A., Hatcher-Ross, J.L., Wertheimer, R &.Kahn, R.S. (2005). Rethinking race/ethnicity, income, and childhood Asthma: racial/ethnic disparities concentrated among the very poor. Public Health Reports, 120, 109-120.

Urbano, F.L.(2008). Review of the NAEPP 2007 Expert Panel Report (EPR-3) on asthma diagnosis and treatment guidelines. Journal of Managed Care Pharmacy, 14(1), 41-49.