Asthma Phenotypes: A Practical Approach to Diagnosis and Treatment

This is a free full text editorial by the former WAO President, Richard Lockey, who teaches that “Asthma is the most treatable of all chronic diseases known to mankind.”

Yet, outcome data from throughout the world indicate that the diagnosis and treatment of asthma are not optimal and need improvement. Why?

Here are 4 reasons:

- asthma is not thought of as a complex, heterogeneous disease or syndrome that consists of different phenotypes and endotypes

- asthma is variable, particularly in its severity, and is influenced by known, unknown, avoidable, and unavoidable environmental factors

- treatment usually requires complex inhalational devices that are difficult to understand and use, and with which adherence is suboptimal

- assessment of asthma is primarily based on symptoms, and, at times, all symptoms are due to asthma, but many times some or all symptoms are due to unrecognized and untreated comorbid or coexisting conditions.

Allergists/immunologists are well suited to provide the type of comprehensive care required to optimize asthma outcomes.


Asthma Phenotypes: An Approach to the Diagnosis and Treatment of Asthma - The Journal of Allergy and Clinical Immunology: In Practice
(free full text)

Omalizumab may have anti-inflammatory effects on small airways and reverse airway remodeling

Omalizumab, a humanized anti-IgE monoclonal antibody, is an effective treatment for severe allergic asthma. This prospective, single-arm observational study, evaluated its effects on small airways and airway remodeling, in 26 adult patients with severe refractory asthma (48 weeks of omalizumab treatment).

Asthma Quality of Life Questionnaire scores and peak expiratory flow improved. Asthma exacerbations requiring systemic corticosteroids, fractional exhaled nitric oxide at 50 mL/s and alveolar nitric oxide levels, sputum eosinophil proportions, and airway-wall thickness as assessed by computed tomography also decreased.

Omalizumab may have anti-inflammatory effects on small airways and reverse airway remodeling.


Comprehensive efficacy of omalizumab for severe refractory asthma: a time-series observational study. Tajiri T et al. Ann Allergy Asthma Immunol. 2014 Jul 1. pii: S1081-1206(14)00405-0. doi: 10.1016/j.anai.2014.06.004. [Epub ahead of print]

What are the diagnostic criteria for hypersensitivity pneumonitis (extrinsic allergic alveolitis)?

Always think of HP in patients with a working diagnosis of asthma whose symptoms do not improve, and there are infiltrates on CXR. The terms hypersensitivity pneumonitis (HP) and extrinsic allergic alveolitis (EAA) are used interchangeably.

Several different diagnostic criteria for HP have been proposed. All have problems that limit their utility, for example:

- All were developed before the common use of high resolution CT scanning and bronchoalveolar lavage
- Most apply only to typical, acute cases
- No clear diagnostic criteria exist for subacute or chronic disease
- All rely on the presence of an abnormal chest radiograph or positive serum precipitins, findings which are often absent

The proposed diagnostic criteria for HP are based upon the presence of some or all of the following:

1. Known exposure to offending antigen(s) identified by:

1-1 History of exposure.
1-2 Aerobiologic or microbiologic investigations of the environment that confirm the presence of an inciting antigen
1-3 presence of specific IgG antibodies in serum against the identified antigen (serum precipitins). A positive precipitin test even in the presence of a clear history of exposure to the identified antigen is merely suggestive of, rather than diagnostic of, a potential etiology.

2. Compatible clinical, radiographic, or physiologic findings:

2-1 Respiratory (or constitutional) symptoms and signs, such as crackles on chest exam, weight loss, cough, breathlessness, febrile episodes, wheezing, and fatigue. These findings are especially suggestive if present, appearing or worsening several hours after antigen exposure.
2-2 Reticular, nodular, or ground glass opacity on chest radiograph or HRCT
2-3 Altered spirometry and/or lung volumes (may be restrictive, obstructive, or mixed pattern), reduced DLCO, altered gas exchange either at rest or with exercise testing.

3. BAL with lymphocytosis:

3-1 Usually with low CD4 to CD8 ratio
3-2 Positive specific immune response to the antigen by lymphocyte transformation testing (currently not available in most centers)

4. Positive inhalation challenge testing by:

4-1 Reexposure to the environment
4-2 Inhalation challenge to the suspected antigen in a hospital setting

5. Histopathology showing compatible changes:

- Poorly formed, noncaseating granulomas OR Mononuclear cell infiltrate

Definite HP - A patient is considered to have definite HP under the following circumstances:

- Criteria 1, 2, and 3 are met – Histopathologic confirmation of the diagnosis is not needed in the majority of such cases.
- Criteria 1, 2, and 4-1 are met – BAL or histopathologic confirmation of the diagnosis is not needed in the majority of these cases but may be important to allow decision-making regarding management.
- Criteria 1, 2-2, 3, and 5 are met – These patients are usually identified as part of a case cluster. The index cases usually have more severe disease.
- Criteria 2, 3, and 5 are met – In these cases, the diagnosis is first suspected after BAL or transbronchial lung biopsy. It is critical that every attempt be made to identify the specific antigen. This often requires aggressive surveillance of the home and work environment by an experienced industrial hygienist. Complete removal of the patient from his or her usual environment for two to three weeks may lead to spontaneous improvement, and reexposure may result in acute symptoms that help identify environmental precipitants.

Probable or subclinical HP - A patient is considered to have probable HP if criteria 1, 2-1, and 3 are present, and subclinical HP if criteria 1 and 3-1 are present. Sensitization, rather than HP, is present in patients who only fulfill criterion 1.

How useful are serum precipitins for diagnosis of HP?

Serum can be assayed for precipitating IgG antibodies against many potential antigens, such as molds, fungi, grain dust, or blood or other secretions from animal sources. Unfortunately, the presence of precipitins does not make a definite diagnosis. As an example, 30-40% of farmers have positive serum precipitins to common causes of HP in the absence of clinical disease. The incidence of serum precipitins in asymptomatic bird breeders is even higher, probably due to more intense and prolonged exposure to inciting antigens.

Another problem is that the absence of serum precipitins does not rule out HP. Also, many routine precipitin panel are virtually useless because of the high rate of falsely negative results.

There is often misunderstanding that skin test reactivity has the same implication as the finding of serum precipitins. However, skin tests are not helpful in the diagnosis of HP.

The relevant antigen to hypersensitivity pneumonitis cannot be identified in up to 20% to 30% of patients

How often are total and specific IgE elevated in HP patients?

In bird fancier HP, specific IgE antibodies were found 18% of parakeet fanciers and 25% of canary fanciers, all of whom had symptoms of rhinitis and/or bronchial asthma. These findings suggest an allergic origin of these symptoms in a percentage of the patients, which would be in agreement with the IgE elevation detected in 28% of a series of 86 patients (

Why is HP predominantly IgG- rather than IgE-mediated disease?

Antigens provoking HP are usually less 3 µm in diameter and are inhaled into the distal bronchial tree and alveoli, where they are cleared via local lymphatic drainage to the hilar nodes, which induces an immunoglobulin‐G (IgG) antibody response. In contrast, antigens more typically associated with asthma are larger, around 30 µm in diameter, and are preferentially deposited in the proximal airways, where they tend to provoke an IgE antibody response in atopic subjects. Nevertheless, a single antigen may sometimes produce both types of response and occasionally, larger particles may reach the alveoli after degradation or being dissolved in lung secretions.


Diagnosis of hypersensitivity pneumonitis (extrinsic allergic alveolitis). UpToDate, 2014.

Hypersensitivity pneumonitis: current concepts. ERJ July 1, 2001 vol. 18 no. 32 suppl 81s-92s.

Bird fancier's lung: a series of 86 patients. Morell F1, Roger A, Reyes L, Cruz MJ, Murio C, Muñoz X. Medicine (Baltimore). 2008 Mar;87(2):110-30. doi: 10.1097/MD.0b013e31816d1dda.

Related reading:

Hypersensitivity pneumonitis (HP)

Green areas around homes reduce atopic sensitization in children

Western lifestyle is associated with high prevalence of allergy, asthma and other chronic inflammatory disorders. ‘Biodiversity hypothesis’ suggests that reduced contact of children with environmental biodiversity, including environmental microbiota in natural habitats, has adverse consequences on the assembly of human commensal microbiota and its contribution to immune tolerance.

This study analysed 4 cohorts from Finland and Estonia with 1,000 children and adolescents aged 0.5–20 yrs. The prevalence of atopic sensitization was assessed by measuring serum IgE specific to inhalant allergens. WProportion of 5 land-use types—forest, agricultural land, built areas, wetlands, and water bodies—in the landscape around the homes was calculated using the CORINE2006 classification.

The cover of forest and agricultural land within 2–5 km from the home was inversely associated with atopic sensitization. This relationship was observed for children 6 years of age and older.

Land-use pattern explained 20% of the variation in the relative abundance of Proteobacteria on the skin of healthy individuals, supporting the hypothesis of a strong environmental effect on the commensal microbiota.

The amount of green environment (forest and agricultural land) around home was inversely associated with the risk of atopic sensitization in children. Early life exposure to green environments is especially important. The environmental effect may be mediated via the effect of environmental microbiota on the commensal microbiota influencing immunotolerance.


Green areas around homes reduce atopic sensitization in children. Lasse Ruokolainen et al. Allergy, 2014, DOI: 10.1111/all.12545.

Small airway disease in asthma

Pathological abnormalities in the peripheral membranous bronchioles less than 2 mm in diameter (i.e. small airways) is found in asthma patients across a spectrum of severity including the 'difficult-to-treat phenotype'.

So far no unanimously accepted method is available for small airway abnormality detection. Recent pharmaceutical developments have led to inhaler devices with smaller aerosol particles and systemic biologic treatments, enabling therapeutic drug delivery to the distal lung regions.


Small airway disease in asthma: pathophysiological and diagnostic considerations. Contoli M, Santus P, Papi A. Curr Opin Pulm Med. 2015 Jan;21(1):68-73.

Small-airway disease in asthma: pharmacological considerations. Usmani OS. Curr Opin Pulm Med. 2015 Jan;21(1):55-67.
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