research paper on asthma

• Open access
• Published: 13 August 2021

Biological therapy for severe asthma

• Silvano Dragonieri   ORCID: orcid.org/0000-0003-1563-6864 1 &
• Giovanna Elisiana Carpagnano 1  

Asthma Research and Practice volume  7 , Article number:  12 ( 2021 ) Cite this article

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Around 5–10% of the total asthmatic population suffer from severe or uncontrolled asthma, which is associated with increased mortality and hospitalization, increased health care burden and worse quality of life. In the last few years, new drugs have been launched and several asthma phenotypes according to definite biomarkers have been identified. In particular, therapy with biologics has revolutionized the management and the treatment of severe asthma, showing high therapeutic efficacy associated with significant clinical benefits. To date, four types of biologics are licensed for severe asthma, i.e. omalizumab (anti-immunoglobulin E) antibody, mepolizumab and reslizumab (anti-interleukin [IL]-5antibody), benralizumab (anti-IL-5 receptor a antibody) and dupilumab (anti-IL-4 receptor alpha antibody). The aim of this article was to review the biologic therapies currently available for the treatment of severe asthma, in order to help physicians to choose the most suitable biologic agent for their asthmatic patients.

Since the beginning of this millennium, asthma assessment and management have been revolutionized. While some new therapeutic approaches have been suggested for mild asthmatics, the most relevant changes have occurred in severe asthma. Severe asthma accounts for the 5–10% of the global asthma population, with 3 to 5% being uncontrolled despite adherence to therapy and proper use of inhalers [ 1 ]. These subjects cannot achieve symptoms control despite maximal therapy with inhaled corticosteroids (ICS) and, quite often, maintenance oral corticosteroids (OCS) are necessary in an endeavor to avoid life-threatening exacerbations [ 2 ]. Although OCS courses remain essential for the management of acute exacerbations, their recurrent or continuous usage is associated with several complications, such as an increased risk of developing osteoporotic fractures and pneumonia [ 3 ]. Moreover, other conditions including cardiovascular and cerebrovascular events, renal dysfunction, diabetes mellitus type 2, humor alterations, obesity and sleep apneas are known to be associated with systemic corticosteroid exposure [ 3 ]. Additionally, many patients remain poorly controlled and show recurrent exacerbations despite a strict adherence to therapy [ 4 ].

The recent advances in our knowledge of the etiopathological mechanisms of different phenotypes and endotypes of severe asthma gave us very innovative therapies, such as biological drugs for severe asthma. These medications are mostly directed against molecules involved in the type 2 inflammatory pathway, thus modifying the natural course of the disease by reducing airways inflammation without the collateral damage associated with corticosteroids. Based on the above, the aim of this article was to review the biologic therapies currently available for the treatment of severe asthma, in order to help physicians to choose the most suitable biologic agent for their asthmatic patients.

Licensed medications for severe asthma

To date, there are five biologic molecules officially approved for use in selected severe asthmatic patients. The first of these is omalizumab, an anti-IgE monoclonal antibody acting through various mechanisms on allergic pathways (Table 1 ). Three more biologics for asthma, belonging to a different class, have been approved, i.e. mepolizumab, reslizumab and benralizumab. They all target the interleukin-5 (IL-5) pathway with the first two targeting the interleukin itself and the last one its receptor. Finally, dupilumab is a monoclonal antibody against the receptor of interleukin-4 (IL-4) which blocks the signaling pathways of IL-4 and IL-13.

BIOLOGICS TARGETING IgE

Omalizumab was the first targeted biologic therapy developed and licensed for severe asthma, being approved by the Food and Drugs Administration in 2003 [ 5 ]. It is a recombinant monoclonal Antibody which binds to IgE, thereby lowering blood IgE levels of up to 99% [ 6 ]. Moreover, It decreases expression of IgE receptor FCRI on inflammatory cells such as mast cells and basophils, thus helping to both mitigate the allergic response and strengthen the antiviral immune response, finally leading to prevent asthma exacerbations [ 7 ]. Omalizumab is approved in adults and children above 6 years old with IgE-driven moderate-to-severe persistent allergic asthma which remains uncontrolled despite GINA step 4/5 treatment, high levels of blood IgE, and documented sensitization to a perennial allergen [ 8 ]. Its dosage varies according to patient’s bodyweight and circulating IgE levels and it is administered subcutaneously every 14 or 28 days [ 9 ]. Although not necessary from a safety point of view, it is advisable to re-evaluate patients after the initial 16 weeks of treatment to assess the drug efficacy before continuing with omalizumab therapy [ 8 ].

The efficacy and safety of omalizumab are nowadays unquestionably recognized, with numerous studies demonstrating that this biological is generally well-tolerated, with no serious adverse effects reported [ 10 , 11 , 12 , 13 , 14 , 15 ]. Common side effects include injection site or diffuse rash, fever, nose bleeding, joint pain, gastro-intestinal disturbances, headache, dizziness and cold symptoms [ 10 , 11 , 12 , 13 , 14 , 15 ]. A Cochrane systematic review assessing 25 randomized controlled trials in patients with allergic asthma showed the efficacy of omalizumab in reducing asthma exacerbations, hospitalizations, and inhaled corticosteroid dosage [ 10 , 15 , 16 , 17 , 18 , 19 ].

During the last few years, a number of biomarkers for monitoring the efficacy of omalizumab therapy have been proposed, including total and antigen-specific IgE, blood eosinophil count and exhaled nitric oxide (FeNO) [ 20 , 21 ]. Surprisingly, total IgE did not appear to be a reliable predictor of response to omalizumab therapy, evidencing that our knowledge on this field is still limited [ 21 ]. Peripheral blood eosinophil count ≥300 cells/mL are linked to higher asthma severity and to a better response to omalizumab [ 22 , 23 ]. Furthermore, patients under omalizumab with higher blood eosinophil count have a higher chance to suffer from asthma exacerbations in case of omalizumab discontinuation [ 24 ]. Regarding FeNO, elevated values at baseline correlated with a better response to omalizumab with regard to exacerbations decrease [ 20 , 25 ]. Likewise, elevated levels of FeNO after suspension of long-term therapy with omalizumab may be a predictor of successive exacerbations [ 24 ].

Biologics targeting IL-5

IL-5 is a well-known regulator of the activation, differentiation, effector function, migration and survival and effector function of eosinophils [ 26 ]. Eosinophil levels associated with symptoms of asthma correlate with disease severity and increase the risk of asthma exacerbations, evidencing that this granulocyte type plays a key role in the pathophysiololgy of asthma [ 26 ]. Currently, licensed biologics against IL-5 pathways are mepolizumab, reslizumab, and benralizumab.

MEPOLIZUMAB

Mepolizumab is a monoclonal antibody directed against IL-5 which has been approved as an add-on treatment for patients ≥6 years old in Europe and for patients ≥12 years old in the USA. Mepolizumab was the first anti-IL-5 antibody approved for the treatment of severe asthma by the Food and Drugs Administration in 2015. Eligible subjects are those with severe eosinophilic asthma that remains uncontrolled despite GINA step 4/5 therapy, with blood eosinophil count of ≥150 cells/μl during the first administration or ≥ 300 cells/μl in the previous year and with at least 2 asthma exacerbations requiring systemic steroid course in the past year [ 27 , 28 ]. Mepolizumab is administered by a subcutaneous injection at a fixed dose of 100 mg every 28 days.

Several studies evaluating mepolizumab for uncontrolled eosinophilic asthma showed a markedly reduction with regard to number of exacerbations, systemic corticosteroid usage, emergency room accesses and hospital admissions, and a concurrent improvement of asthma controls and lung function parameters [ 29 , 30 , 31 , 32 , 33 ].

Furthermore, a number of studies revealed that mepolizumab has a positive long-term safety profile [ 34 , 35 , 36 ]. No reports of mepolizumab-associated anaphylaxis reactions were documented, as well as parasitic infections [ 34 , 35 , 36 ]. Common side effects include headache, injection site reaction, fatigue, flu symptoms, urinary tract infection, abdominal pain, itching, eczema, and muscle spasms [ 34 , 35 , 36 ].

Additionally, numerous investigations highlighted that the most important markers of response prediction to mepolizumab are the rate of previous exacerbation and baseline peripheral blood eosinophil count [ 29 , 32 , 37 , 38 , 39 ]. Indeed, a better clinical efficacy is directly proportional to a higher eosinophil count and to a higher rate of exacerbations [ 29 , 32 , 37 , 38 , 39 ]. Interestingly, mepolizumab effectiveness was not related to baseline IgE and to atopy [ 40 , 41 ] and earlier treatment with omalizumab is not a predictor for mepolizumab efficacy [ 42 , 43 , 44 ].

There is a lack of consensus about the duration of treatment before evaluating the effectiveness of mepolizumab. Actually, the GINA statement suggests that a 4-month trial may be adequate [ 8 ], whereas the NICE guidelines recommend that mepolizumab should not be discontinued before 12 months of therapy and that drug-responsiveness should be assessed every year [ 45 ].

Reslizumab is monoclonal antibody approved in 2016, which binds with high-affinity to IL-5 [ 46 ]. By an analogous mechanism of action to mepolizumab, reslizumab lowers circulating blood eosinophil levels [ 47 ]. It has been approved for patients ≥18 years old with severe eosinophilic asthma which remains uncontrolled despite therapy with high-doses of ICS plus another inhaler. Reslizumab is indicated in patients with ≥400 eosinophils/μl and history of asthma exacerbations in the previous 12 months [ 48 , 49 ]. Reslizumab is administered intravenously every 28 days at a weight-based dose of 3 mg/kg.

Similarly to mepolizumab, studies assessing reslizumab have shown a decreased number of asthma exacerbations and improved asthma control and lung function parameters in subjects with high blood eosinophil levels [ 47 , 50 ].

The safety profile of reslizumab has been evaluated for up to 24 months, revealing minor adverse effects without any reports of parasitic and opportunistic infections [ 51 ]. Most frequent side effects include cough, dizziness, itching, skin rash and fatigue [ 51 ].

However, despite its proven excellent clinical efficacy, intravenous formulation has a significant impact on the ease of administration compared to mepolizumab and/or benralizumab. Studies using reslizumab showed unsatisfactory results, without significant improvements in terms of acute exacerbations reduction or OCS lowering [ 52 ].

BENRALIZUMAB

Benralizumab is a monoclonal antibody approved in 2017 and directed against IL-5 receptor a (IL-5Ra) which induces eosinophil apoptosis via the antibody-dependent cell-mediated cytotoxicity (ADCC) involving natural killer cells, leading to peripheral blood eosinophil depletion [ 53 , 54 ]. Benralizumab acts like a competitive inhibitor to IL-5, binding with higher affinity to the a-subunit of IL-5Ra, which is expressed on mature (and precursors) eosinophils and basophils [ 55 ].

This biologic drug is licensed as an add-on treatment for uncontrolled severe eosinophilic asthma in patients ≥18 years with ≥300 blood eosinophils/μl [ 56 , 57 ]. A 30 mg dose of benralizumab is injected subcutaneously every 28 days for the first 3 administrations and afterwards every 56 days.

Large studies evaluating benralizumab in patients with moderate to severe asthma have shown a decrease in exacerbations number, improved lung function, and reduced use of OCS [ 53 , 54 , 58 ]. Combined analysis of these investigation have revealed that the best predictors of response to benralizumab are adult-onset asthma, more than 3 exacerbations in the previous year, nasal polyposis and pre-bronchodilator FVC < 65% of predicted [ 53 , 54 , 58 ].. The most common adverse effect were fever after the first injection, headache and pharyngitis [ 53 , 54 , 58 ].

Interestingly, based on its mechanism, benralizumab almost completely depletes blood eosinophils within 24 h of administration and a total depletion of airway eosinophils compared to that caused by mepolizumab [ 59 , 60 ]. Likewise, nasal eosinophils were totally suppressed after 6 months of therapy with benralizumab [ 61 ].

Recently, some concerns have been raised about the theoretical risks following an eosinophil depletion, especially with respect to host defense. However, these warnings were not confirmed, since it appears that there is adequate redundancy within human immune apparatus, which is not impaired by eosinophils depletion [ 62 ].

Biologics targeting IL-4 and IL-13

IL-4 and IL-13 are two interleukins which regulate and drive Type-2 inflammation. IL-4 increases the Th-2 cell population and B-cell isotype rearrangement of IgE as well as promoting eosinophilic transmigration through endothelium, whereas IL-13 plays an important role in asthma by promoting airway hyperresponsiveness, mucus secretion and airway remodeling [ 63 , 64 ]. Thus far, the only licensed drug acting on the two aforementioned ILs is dupilumab.

Dupilumab is a monoclonal antibody approved in 2018 which binds to the IL-4 receptor alpha-subunit, mutual to IL-4 and IL-13 receptors and inhibits both IL-4 and IL-13 pathways. Dupilumab is licensed as an add-on maintenance therapy in asthmatic patients GINA step 4/5 ≥ 12 years with type 2 inflammation characterized by increased blood eosinophils and/or raised FeNO. Dupilumab is administered subcutaneously at a starting dose of two injections of 200 mg each (total 400 mg), followed by one injection of 200 mg every 14 days, or at a starting dose of 600 mg (two injections of 300 mg each) followed by 300 mg every 14 days. The latter regimen is recommended for asthmatic subjects strictly dependent from OCS or with atopic dermatitis [ 65 ]. Dupilumab is also indicated for moderate to severe atopic dermatitis and for nasal polyposis.

A number of studies have demonstrated that therapy with dupilumab in severe asthmatics lowers the number of asthma exacerbations, improves lung function parameters and asthma control test scores, and lowers the use of OCS, irrespective of peripheral blood eosinophil count [ 66 , 67 , 68 , 69 ]. Indeed, a transitory increase of blood eosinophilia at the beginning of treatment with dupilumab has been observed although it may be due to blocked migration into tissues rather than hyperproduction [ 69 ]. Furthermore, reduced levels of T2 inflammation markers, including FeNO, serum levels of eotaxin-3, periostin and thymus and activation regulated chemokine (TARC) and total IgE, may serve as parameters for monitoring the efficacy of therapy with dupilumab [ 66 , 67 , 68 , 69 ]. The most common adverse reactions were injection site reactions, various types of infections, conjunctivitis and related conditions [ 66 , 67 , 68 , 69 ].

Biologics under development

Research for next-generation biologics is ongoing. Currently, other effector molecules are under the spotlight as new targets for perspective biological therapies, particularly the so-called alarmins [ 70 ]. These molecules are released by the airway epithelium against the harmful actions of germs, pollutants, allergens and cigarette smoke.

Tezepelumab is a human monoclonal antibody which binds to thymic stromal lymphopoietin (TSLP), an epithelium-derived alarmin that plays a relevant role in the pathogenesis of asthma, being an upstream effector T2-high pathobiologic pathways [ 71 , 72 , 73 ]. With the presence of tezepelumab, TLSP cannot bind to its receptor [ 74 ] hence inhibiting downstream signaling. A number of phase 2 and 3 trials have clearly shown that patients with severe uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo [ 75 , 76 ]. Concerning its safety profile, neither investigational tezepelumab-related anaphylactic reactions nor the detection of neutralizing antibodies were reported [ 75 , 76 ]. To date, license application for tezepelumab has been accepted and granted Priority Review for the treatment of asthma from the US Food and Drug Administration, whose regulatory decision is expected during the first quarter of 2022.

Ipetekimab is a monoclonal antibody targeting IL-33, another alarmin which associates with TSLP leading to an activation of T2-high inflammatory pathway in asthma [ 77 ]. Phase 2 studies with this biologic are ongoing, however preliminary results did not show adequate efficacy in severe asthmatics when associated with dupilumab or vs dupilumab alone [ 70 ].

Moreover, Tralokinumab and lebrokizumab are monoclonal antibodies both targeting IL-13 alone with disappointing results of phase 3 studies in terms of exacerbations reduction and OCS sparing in severe asthmatics [ 78 ].

Finally, regarding Th2-low asthma, mainly characterized by a neutrophilic airways inflammation, efforts are focusing on its pathogenic cascade involving cytokines such as IL-1beta, IL-17 and IL-23. Several monoclonal antibodies against the aforementioned interleukins such as canakinumab (anti IL-1beta), brodalumab (anti IL-17 receptor) and risankizumab (anti IL-23) are under evaluation with phase 1–2 trials showing controversial results [ 79 , 80 , 81 ].

Which biologic should I choose for my asthmatic patient?

When choosing a biologic medication for their patients with severe uncontrolled asthma, clinicians should always take into account the asthma endotype, clinical biomarkers, and patient-focused aspects (Fig 1 ).

Algorithm for Selecting Ideal Biologic Treatment for severe uncontrolled asthma

Omalizumab should always be the first biological option in allergic non-eosinophilic severe asthmatics, with high levels of blood IgE, and with at least a documented positivity to a perennial aeroallergen. Contrariwise, patients with a non-allergic eosinophilic phenotype should be treated with an anti-IL-5 biological drug. Finally, anti- IL-4/IL-13 should be reserved to patients with severe eosinophilic type 2 asthma OCS dependent [ 8 ].

Given to the a lack of comparison studies, to date there are no recommendations about the selection of appropriate anti IL-5 biologic drug among those available. Hence, the choice is empirical and possibly shared between physician and patient.

According to GINA guidelines, a (at least) 4-month trial should be carried to evaluate asthma control. In the event of poor asthma control, a switch to a different biological treatment can be attempted if the patient meets the eligibility criteria.

Nevertheless, the right time and the right modality of switching from one biologic to another and the treatment time are still unknown. Large studies focused on biological drug switch in patients with severe asthma are ongoing and will help physicians to ease therapeutic strategies.

Conclusions

Severe asthma accounts for a small proportion of total asthma cases, but impose a heavy burden on health care system. Recent revelations of the T2 inflammatory pathways and the development of monoclonal antibodies acting on the T2 cascade has completely revolutionized the management of severe asthma, by introducing new, life-improving treatment options for this class of patients. This paves the way for a biomarker-driven personalized medicine. Strictly following GINA recommendations, the categorization of T2 molecular targets has allowed the identification of patients with severe asthma who would likely respond to specific biological molecules. However, the most suitable biological option for severe asthmatics with overlapping phenotypes is still unclear, thus requiring further discriminatory and predicting biomarkers which may allow a better patient selection.

Availability of data and materials

Not applicable.

Abbreviations

interleukin

inhaled corticosteroids

oral corticosteroids

immunoglobulin E

fractional exhaled nitric oxide

forced vital capacity

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A systematic review of psychological, physical health factors, and quality of life in adult asthma

• Sabina Stanescu   ORCID: orcid.org/0000-0003-0792-8939 1 ,
• Sarah E. Kirby 1 , 2 ,
• Mike Thomas   ORCID: orcid.org/0000-0001-5939-1155 2 , 3 ,
• Lucy Yardley 1 &
• Ben Ainsworth 4  

npj Primary Care Respiratory Medicine volume  29 , Article number:  37 ( 2019 ) Cite this article

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• Outcomes research
• Quality of life

Asthma is a common non-communicable disease, often characterized by activity limitation, negative effects on social life and relationships, problems with finding and keeping employment, and poor quality of life. The objective of the present study was to conduct a systematic review of the literature investigating the potential factors impacting quality of life (QoL) in asthma. Electronic searches were carried out on: MEDLINE, EMBASE, PsycINFO, the Cochrane Library, and Web of Science (initial search April 2017 and updated in January 2019). All primary research studies including asthma, psychological or physical health factors, and quality of life were included. Narrative synthesis was used to develop themes among findings in included studies in an attempt to identify variables impacting QoL in asthma. The search retrieved 43 eligible studies that were grouped in three themes: psychological factors (including anxiety and depression, other mental health conditions, illness representations, and emotion regulation), physical health factors (including BMI and chronic physical conditions), and multifactorial aspects, including the interplay of health and psychological factors and asthma. These were found to have a substantial impact on QoL in asthma, both directly and indirectly, by affecting self-management, activity levels and other outcomes. Findings suggest a complex and negative effect of health and psychological factors on QoL in asthma. The experience of living with asthma is multifaceted, and future research and intervention development studies should take this into account, as well as the variety of variables interacting and affecting the person.

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Introduction

Over 235 million people worldwide are living with asthma, which is one of the leading non-communicable diseases worldwide. 1 , 2 Symptoms, exacerbations, and triggers in asthma are associated with lower quality of life (QoL), tiredness, activity limitation, negative effects on social life and relationships, problems with finding and keeping employment, and reduced productivity. 3 , 4 , 5 , 6 , 7 People with asthma are up to six times more likely than the general population to have anxiety or depression, 8 and 16% of people with asthma in the UK have panic disorder, 9 compared to 1% in the general population. 10 People with brittle asthma (difficult-to-control asthma with severe, recurrent attacks) demonstrate even greater comorbidity and maladaptive coping styles. 11 Psychological dysfunction is often unrecognized in primary care, despite being significantly associated with poor asthma outcomes, including asthma control and QoL. 8 , 12 , 13 Indeed, the European Asthma Research and Innovation Partnership has identified understanding the role of psychological factors as an unmet need in improving asthma outcomes. 14 , 15 They propose that anxiety and depression are present at all three stages of the experience of asthma: onset, progression, and exacerbation. 14

A recent meta-analysis found that asthma diagnoses significantly increased the risk of psychological and health conditions (such as cardiovascular/cerebrovascular diseases, obesity, hypertension, diabetes, psychiatric and neurological comorbidities, gut and urinary conditions, cancer, and respiratory problems other than asthma). 16 In addition, studies have pointed towards an impact on QoL in people with asthma of additional health and psychological factors, such as comorbid anxiety or depression, higher body mass index(BMI), professional status, and feelings of lack of control over health (for example, refs 17 , 18 ). Such evidence reinforces the argument that the needs of people with asthma should be approached in conjunction with these additional factors, rather than using a single-illness approach, aiming to reduce the adversity of people’s experience. However, the extent to which psychological and physical health factors interact and impact asthma outcomes is yet to be systematically explored. This systematic review aims to provide a narrative synthesis of the literature exploring psychological and physical health factors that influence QoL in adults with asthma.

Study characteristics

The search and screening process identified 43 eligible papers, published between 2003 and 2019 (see Fig. 1 for PRISMA flowchart 19 ). The characteristics of each study are summarized below in Table 1 . Twelve studies were conducted in Europe, 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 17 in North America, 12 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 7 in Australia, 17 , 48 , 49 , 50 , 51 , 52 , 53 4 in Asia, 54 , 55 , 56 , 57 and 3 in Africa. 58 , 59 , 60 All papers employed a quantitative approach comprising 2 longitudinal studies 31 , 44 and 41 cross-sectional studies. Only 4 studies included a control group. 21 , 28 , 29 , 31 Overall, the majority of papers had a large sample size (ranging between 40 and 39,321 participants; 30 papers included a sample size of >100). The majority of studies recruited from primary care or the general population, using self-report to confirm a diagnosis of asthma. Only a few studies recruited from secondary and tertiary asthma clinics. 12 , 27 , 36 , 41 , 44 , 48 , 60 There was a high occurrence ( n  = 14) of exclusion criteria relating to specific demographic or asthma characteristics, as well as mental health conditions and comorbidities, which restricted the study sample without a reason being given. Most studies used self-report measures, 17 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 39 , 41 , 42 , 43 , 44 , 45 , 46 , 48 , 49 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 with a small proportion using psychiatric interviews to screen for mental health conditions. 12 , 31 , 38 , 40 , 50 The majority of studies used asthma-specific QoL measures ( n  = 29), 12 , 21 , 23 , 25 , 27 , 28 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 39 , 40 , 41 , 42 , 44 , 48 , 49 , 50 , 51 , 54 , 55 , 56 , 58 , 59 , 60 , 61 17 included an health-related QoL measure ( n  = 18), 17 , 20 , 22 , 23 , 24 , 25 , 28 , 30 , 31 , 34 , 35 , 36 , 38 , 43 , 50 , 51 , 52 , 55 and 4 used general measures of QoL ( n  = 7); 26 , 35 , 45 , 46 , 47 , 57 , 62 11 papers used >1 measure of QoL. 23 , 25 , 28 , 30 , 34 , 35 , 36 , 37 , 50 , 51 , 55 The average age across included studies was 42.1 years (and 61.57% were female). Papers report prevalence rates of between 16.8% and 48.9% for depression and between 13.3% and 44.4% for anxiety, 20 , 27 , 33 , 38 , 50 , 56 , 58 , 60 with an average of 28.31% for a diagnosis of anxiety or depression. Across several studies, the prevalence of other mental health conditions was 28.31% on average (ranging between 28% and 80%). 12 , 37 , 38 , 40 , 42 Between 72% and 86.9% of people with asthma had at least one additional physical condition and between 21% and 26.3% had ≥2; 25 , 34 , 56 26.36% had, on average, at least one other physical health condition. On average, people with asthma were significantly more likely to have a BMI of >30 (and between 61% and 75.1% had a BMI >25). 26 , 45 , 59 The quality assessment identified that most studies were of a reasonable quality; however, it should be noted that some measures used could be considered inappropriate for the research aim or the population under investigation. Examples include measuring general QoL with an asthma-specific measure or administering a geriatric depression questionnaire to a young adult population.

PRISMA statement of included and excluded papers

Narrative synthesis

Narrative synthesis generated three overarching themes: psychological factors, health factors, and multifactorial aspects (see Table 2 for themes and subtheme descriptions). Overall, patients with asthma demonstrated impaired QoL, which was further decreased by psychological factors (e.g. anxiety, depression, emotion regulation, illness perceptions), health risk factors (such as an increased BMI), and the presence of a co-existing mental health or physical condition (such as rhinitis, cardiovascular disease, diabetes, etc.). Having more than one co-existing condition or psychological factor impacted overall QoL even more substantially. Results for each of the aspects found are presented below.

Psychological factors

Within this first theme, four subthemes were generated. These comprised ‘anxiety and depression’, ‘other mental health conditions’, ‘emotional regulation’, and ‘illness representations’.

Anxiety and depression were notably the most commonly considered factors ( n  = 30). A high prevalence of people with asthma showed symptoms of or clinical diagnoses of anxiety or depression, which appeared to play a key role in understanding the relationship between asthma and QoL. Overall, having a diagnosis of anxiety or depression was associated with poorer QoL across all dimensions (e.g. activity limitation, physical or mental wellbeing, social or role functioning, etc.), as well as health perceptions. 24 , 36 , 46 , 50 , 54 In particular, one study (of undergraduate students aged 18–25 years, with childhood-onset asthma) found that anxiety was significantly associated with asthma QoL, as was the interaction between anxiety and depression, 32 while others found that generally anxiety and depression both predicted worse QoL independently (refs 12 , 29 , 33 , 38 , 42 , 44 , 56 , 60 ). One study found that the average asthma-related QoL scores for people with asthma and depression were 1.4 times lower compared to people with asthma and no depression. 33 Having current depression or anxiety was associated with worse QoL than was having a lifetime diagnosis; this was in turn was greater than having no depression or anxiety. 45 Having a history of major depression was also significantly associated with worse physical and mental functioning, compared to those with asthma and no depression. 38 There was considerable variability across variance explained, with depression found to account for between 3% 40 and 56% 30 of the variance in QoL, whereas anxiety was found to account for between 2% 40 and 68%. 21

In contrast, one study found that having either a depressive or an anxiety disorder significantly impacted asthma QoL but having both was not significantly different than only having one, 40 which is dissonant with other studies. Another study of 90 people with difficult asthma found that having anxiety or depression had no significant effect on QoL. 48 In addition, although depression was associated with poorer QoL, it did not inflate the relationship between asthma severity and QoL. 29 All other studies were significant but showed only small-to-moderate effect sizes. Having a full clinical diagnosis of anxiety or depression was not significantly worse (in terms of QoL) than having only some symptoms of anxiety and depression.

Studies also considered the impact of anxiety and depression on specific subdomains of QoL and asthma-specific QoL. Having anxiety was not associated with physical functioning, mental health or health perception, 38 or the physical component of QoL. 20 Depression, however, was associated with significantly poorer QoL on physical dimensions and activity limitation, 20 , 21 , 23 , 30 , 38 , 45 , 53 , 55 , 58 although one study found significant results only for participants with uncontrolled asthma. 22 In relation to asthma-specific QoL, depression and anxiety were significantly associated with decreased asthma-specific QoL. 17 , 21 , 23 , 27 , 28 , 32 , 33 , 36 , 37 , 40 , 50 , 54 , 55 , 58 , 61

Nine studies looked at other mental health conditions, such as panic disorder with or without agoraphobia, 24 , 38 , 44 , 57 personality disorders, 31 alexithymia, 23 somatization, 38 mood disorders, 12 , 40 , 57 schizophrenia, eating disorders, substance use disorders, 38 and general occurrence of any psychiatric disorder. 12 , 17 The results in this subtheme were mixed, but overall they suggest that the presence of an additional mental health condition is significantly associated with a decrease in QoL in patients with asthma. 12 , 17 Panic disorder was also shown to be both significantly 24 and non-significantly 57 associated with poorer mental and physical components of QoL. Alexithymia in people with asthma was not associated with poorer QoL. 23 Having asthma and a personality disorder was associated with lower general QoL, 31 as well as lower scores for physical health, vitality, pain, general health, social function, mental health, and emotional role (physical function was not significant). This association was not found for people without asthma, suggesting that it is the combination of conditions (asthma and co-existing mental health conditions) that may lead to the negative impact on QoL. 31

The emotion regulation subtheme included studies that explored the relationship between emotional states, negative affect (not related to anxiety, depression, or other mental health conditions), or coping and QoL in people with asthma. QoL in asthma was found to be influenced by affect and a predisposition to negative states, as found by four studies. 28 , 39 , 41 , 51 For instance, a model of age, gender, negative affect, and medical problems accounted for 20% of symptoms and 23% of activity limitation. 39 This was supported by findings that negative mood is associated with poor scores on both the mental and physical components of the Asthma Quality of Life Questionnaires (AQLQ), 28 as well as a positive correlation between active coping and asthma QoL. 51 Despite heterogeneity, the impaired QoL was associated with impulsive-careless coping 41 and avoidant coping. 51 Overall, the presence of psychological distress seemed to affect people with asthma more than people without asthma in terms of QoL.

Illness-related cognitions are people’s patterns of beliefs about the characteristics of their conditions, which in turn influence their appraisal of severity and can determine future behaviours. 63 A number of illness-related cognitions and perceptions significantly predicted QoL in seven studies. 26 , 34 , 37 , 42 , 43 , 51 , 60 For instance, asthma self-efficacy 42 was positively associated with QoL. However, decreased QoL was significantly predicted by a series of varied illness perceptions: subjective illness severity, uncertainty in illness, illness intrusiveness, 43 perceived disability, 60 health beliefs and attitudes, 34 perceived severity, 34 level of confidence or self-efficacy in managing asthma, 51 satisfaction with illness, 51 anxiety sensitivity for physical concerns, 39 and satisfaction with life. 37 In addition, a model of subjective and objective illness severity accounted for 24% of the variance in QoL, further supporting the effect of illness perceptions on QoL. 34

Physical health factors

Two subthemes were generated in the physical health factors theme: additional physical conditions and BMI.

Ten papers examined additional physical conditions in relation to QoL in asthma; 25 , 27 , 34 , 39 , 46 , 47 , 48 , 49 , 52 , 53 most only referred to ‘comorbidity’ or ‘medical problems’ as a measure of frequency of additional conditions. 34 , 36 , 39 Some studies looked at both general and individual co-existing conditions 25 , 48 , 52 and others counted chronic conditions but did not include them in further analyses. 33 , 36 , 56 , 59 Of the ones that did explore individual conditions, the highest impact seemed to be provoked by musculoskeletal conditions. 25 Similarly, statistically and clinically significant decreases in activity levels were also found for people with asthma and multimorbid conditions. 52 Other conditions investigated included respiratory conditions, 47 diabetes, 25 , 48 obesity, 48 hypertension, 25 , 39 gastro-oesophageal reflux disorder, 48 rhinitis, 48 , 49 vocal cord dysfunction, 48 sleep apnoea, 48 musculoskeletal disorders, 25 , 39 arthritis, 39 , 52 heart disease, 25 stroke, 39 , 52 cancer, 39 , 52 osteoporosis, 52 dysfunctional breathing, 48 headaches, 39 and allergic status. 27 , 39 The consensus was that having an additional physical condition significantly decreased QoL in asthma, the effect being amplified with the addition of further conditions.

Eleven papers exploring BMI found that it consistently influenced QoL for people with asthma both directly as a multimorbid factor and indirectly by increasing the chance of additional conditions and activity limitation. 25 , 26 , 28 , 29 , 35 , 42 , 44 , 45 , 48 , 56 , 59 In particular, one study found that generic health status decreased for overweight and obese patients with asthma. People with asthma with obesity had on average 5.05 more restricted activity days than people without obesity or without asthma. 35 Other studies found that increased BMI was an independent factor in predicting poorer QoL 48 and that QoL was two times worse in overweight and three times worse in obese people with asthma. 59 In contrast, one study found that overweight BMI made no difference; however, being obese did. 27 Almost ½ of obese patients and 25% overweight patients had problems with mobility, pain, discomfort, self-care, and usual activities (compared to <15% people with asthma of normal weight). 26

Multifactorial aspects

Seven studies included statistical analyses to explore potential mechanisms for the relationship between asthma QoL and additional physical conditions, BMI, and psychological factors. 17 , 35 , 42 , 45 , 50 , 56 , 59 Results from studies in this group are complex, indicating that people with asthma are at a higher risk of adverse outcomes (such as exacerbated symptoms or decreased QoL) if they also have a high BMI and depression. 35 , 42 , 56 , 59 People with current depression and asthma are more likely to be obese and 3.9 times more likely to report fair or poor general health. 45 A few of these studies have explored the relationship between these factors further. For example, people with asthma and obesity were more likely to have additional physical comorbidities and poorer QoL. 59 Significant increases in major depression were associated with dyspnoea, 50 and depression and perceived control of asthma significantly mediated between BMI and QoL. 35 Higher BMI has also been associated with worse asthma-specific self-efficacy, which was in turn associated with decreased QoL. 42

The aim of the present review was to synthesise the literature exploring health and psychological factors that influence QoL in adults with asthma. Previous evidence shows that QoL is generally lower in people with asthma and compounded by poor asthma control and severity. 13 The narrative synthesis in the present study builds on this by identifying three themes, encompassing a number of factors that substantially explain further impairment in QoL for people with asthma. These were not limited to individual components but also combinations of co-existing conditions, risk factors, and health and psychological factors, which consistently showed a negative impact on QoL.

Anxiety and depression were the most commonly reported psychological factors associated with impaired QoL, but effects were also found for other mental health conditions, illness representations, and emotion regulation. These results are generally consistent with previous research showing not only that among people with asthma there are more people with depression than without 8 but also with an increase in depression, the risk of asthma increased. 64 Although the relationship between anxiety and depression and asthma-specific QoL were not further considered in the primary sources, they point towards either a link with activity limitation or a cumulative impact of the interaction between these psychological factors, which in turn affect the QoL of people with asthma. In addition, it is argued that people with asthma use more emotion-focused, and generally maladaptive, coping strategies, such as avoidance. 65 Despite this, psychotherapy, such as cognitive-behavioural therapy and counselling has had limited effectiveness in improving asthma outcomes. 66

Physical health factors, such as high BMI and co-occurring health conditions, were extremely common in people with asthma, consistent with existing literature. 16 This affects QoL both directly and indirectly, affecting self-management and illness perceptions. As such, non-pharmacological treatments such as lifestyle change and activity promotion could prove effective. For instance, a higher proportion of people with asthma seem to have overweight or obese BMI 67 and weight loss intervention studies have been associated with improvements in asthma symptoms. 68

One of the fundamental components of reduced QoL is activity limitation, which is especially relevant to people with asthma, with or without additional conditions or psychological risk factors. This has been widely acknowledged by previous research, to the extent that it has been included as one of the components of asthma-related QoL measures, such as the AQLQ. 69 Furthermore, it is not surprising that decreased QoL in adults with asthma is associated with depression or high BMI, both of which have been consistently associated with activity limitation (e.g. refs 70 , 71 ). In addition, depression was found to affect QoL on the physical components as well as the mental ones, which has interesting implications for future research and clinical practice.

It is important to note the high prevalence of anxiety, depression, and chronic conditions, despite frequent exclusion of comorbid psychiatric conditions. This was found throughout the included papers and is consistent with previous research (e.g. refs 8 , 16 ). This does not only mean that psychological and health factors significantly add to the burden of living with asthma but also that the occurrence of psychological dysfunction and health risk factors seem to be common in people with asthma. In addition, the complex nature of patients with chronic diseases such as asthma, with factors interacting, adds to the negative experience of living with asthma. Results are similar to previous meta-analyses and reviews, 8 , 72 pointing towards conclusive evidence that additional factors (physical or psychological) decrease QoL and functionality in asthma. Finally, these effects were consistent, regardless of the measure of QoL used (asthma specific, health related, or general). This suggests that the identified factors may affect people with asthma more than people without asthma or that the cumulative impact of comorbidities is greater than arithmetically assumed.

The quality of the present review needs to be discussed in relation to the methodology and robustness of the synthesis, determined by the quantity and quality of individual studies included. 73 The quality assessment identified that most studies were of a reasonable quality overall, although all papers had one or two elements that were of a slightly lower quality (this included aspects such as recruitment from only one hospital reducing generalizability or self-report vs objective measurement of weight for BMI calculations). However, this was not problematic for the purposes of this review as the focus was to identify potential factors considered in research rather than classify the methodological quality used to measure their impact on QoL. In addition, the search terms in this review could have limited the number and kind of studies included. For instance, not every potential comorbid condition was listed. This could be a focus for future research. Socio-demographic factors were not included, which can be considered a limitation; however, the breadth of the area was deemed too much for the scope of the present review and could also be the focus of future research. The majority of included studies were observational and as such could not be used to determine causal mechanisms. However, the aim of this review was only to identify potential factors involved in decreased QoL in asthma, rather than build a causal model. Similarly, the impact of individual factors was not measured and could be explored in future research.

A strength of the present review is that it uses a novel approach to QoL in asthma, by systematically taking into account additional aspects that influence the experience of living with asthma and impact QoL. Results suggest both a direct association of the identified aspects, as well as indirectly through interactions with other aspects of living with asthma, such as overarching illness perceptions and activity limitation. The present review emphasizes some interesting and novel findings for asthma and QoL research. Three main implications for future research and practice are proposed. First, for future research, the findings of this review should be used to further explore and understand the factors impacting QoL in people with asthma. It is crucial to explore the needs and experience of patients with complex medical problems, in order to unpick the different factors impacting on QoL. Second, the results are relevant for practitioners, particularly in primary care, as they draw attention to the prevalence of various physical and mental health factors that can interact and affect asthma outcomes. This could influence training or guidelines on potential factors to consider during appointments and consultations. Finally, most current non-pharmacological interventions for patients with chronic conditions tend to overlook the complex needs of patients in a multimorbidity context. As such, it is suggested that future intervention development should use a personalized, tailored approach that aims to address the needs of patients with complex medical problems in the wider context of their experience of living with asthma.

This review demonstrates that the themes and factors identified through inductive narrative synthesis illustrate that QoL in asthma cannot be determined in a simplistic way. The findings suggest a complex experience in living with asthma, one that has a stronger impact on QoL than the sum its of parts. People with asthma and their QoL cannot be viewed separately from the psychological and other health elements that they experience. Future research is encouraged to take a function-oriented approach to QoL in asthma, including management of multimorbid conditions when planning studies; clinical practice should also acknowledge the additional and complex needs of people with asthma by offering relevant, person-based tailored interventions.

Search strategy

The initial search was carried out in April 2017 and was updated in January 2019. Databases searched included MEDLINE, EMBASE, PsycINFO, the Cochrane Library, and Web of Science. Search terms used comprised a combination of the following key terms: asthma (MESH term), psychological/psychosocial and factor/determinant/predictor, comorbid, multimorbid, anxiety, depression, illness perception, illness cognition, illness representation, locus of control, self-efficacy, risk factor, quality of life, health-related quality of life, wellbeing, distress, health status, burden. In addition, a hand search of all the references of included papers was performed as well as a grey literature search on Google Scholar.

Study selection

Studies were included if they investigated psychological or physical health factors and included QoL in adults with asthma as primary or secondary outcome. Psychological factors were considered any modifiable factors, including thoughts, beliefs, attitudes, or emotions of people with asthma, as well as the presence of any co-occurring mental health condition. Physical health factors were defined as any physical comorbid or multimorbid condition or risk factor. These were chosen to allow as much inclusivity as possible and to reflect the exploratory nature of this review. Intervention studies were excluded, as they rarely considered the impact of health or psychological factors on QoL but rather investigated how interventions improved asthma outcomes. Studies were excluded if they were conference abstracts, reviews, or not primary research or the full text not in English, German, or Spanish language.

Data extraction and quality appraisal

Data extracted comprised authors, year of publication, study sample, predictors, QoL measurement (outcome), and findings. The AXIS tool 74 was used to assess the quality of included papers. This contains questions on study design, sample size justification, target population, sampling frame, sample selection, measurement validity and reliability, and overall methods and does not offer a numerical scale. No papers were excluded or weighted based on the quality assessment.

Data synthesis

Owing to heterogeneity of QoL measures and the range of variables used in the included studies, narrative synthesis was used to describe and group similar findings, explore patterns identified in the literature, and develop a narrative account of the results. 73 This is an approach to systematic reviews involving the synthesis of findings from multiple sources and relies primarily on word and text to summarise the findings.

All data generated or analysed during this study are included in this published article.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

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S.S.—conception of the review, synthesis, wrote the first draft, commented on drafts. B.A. and S.K.—conception of the review and day-to-day conduct of the review, commented on drafts, updated the review, revised the paper. M.T.—conception of the review, commented on drafts. L.Y.—conception of the review, commented on drafts. All authors read and approved the final version of the manuscript.

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Stanescu, S., Kirby, S.E., Thomas, M. et al. A systematic review of psychological, physical health factors, and quality of life in adult asthma. npj Prim. Care Respir. Med. 29 , 37 (2019). https://doi.org/10.1038/s41533-019-0149-3

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Affiliations.

• 1 Faculty of Medicine, Transylvania University, Brasov, Romania.
• 2 Allergy Unit, IBIMA-Regional University Hospital of Malaga, UMA, RETICS ARADyAL, BIONAND, Malaga, Spain.
• 3 Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
• 4 Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland.
• 5 All-MED Medical Research Institute, Wroclaw, Poland.
• 6 Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
• PMID: 34392546
• DOI: 10.1111/all.15054

Last year brought a significant advance in asthma management, unyielding to the pressure of the pandemics. Novel key findings in asthma pathogenesis focus on the resident cell compartment, epigenetics and the innate immune system. The precision immunology unbiased approach was supplemented with novel tools and greatly facilitated by the use of artificial intelligence. Several randomised clinical trials and good quality real-world evidence shed new light on asthma treatment and supported the revision of several asthma guidelines (GINA, Expert Panel Report 3, ERS/ATS guidelines on severe asthma) and the conception of new ones (EAACI Guidelines for the use of biologicals in severe asthma). Integrating asthma management within the broader context of Planetary Health has been put forward. In this review, recently published articles and clinical trials are summarised and discussed with the goal to provide clinicians and researchers with a concise update on asthma research from a translational perspective.

Keywords: asthma; biomarkers; endotypes; exacerbations; guidelines.

© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

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• Artificial Intelligence
• Asthma* / diagnosis
• Asthma* / drug therapy
• Asthma* / epidemiology
• Biological Products*
• Biological Products

• Open access
• Published: 28 March 2024

Evaluation of adherence to guideline-directed therapy and risk factors for exacerbation in mild asthma: a retrospective chart review

• Beth A. Zerr   ORCID: orcid.org/0000-0002-6011-2923 1 ,
• Jacklyn M. Kruse 2 &
• Jon J. Glover 3  

Allergy, Asthma & Clinical Immunology volume  20 , Article number:  27 ( 2024 ) Cite this article

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A significant update was made to both the Global Initiative for Asthma (GINA) in 2019 and the National Heart Lung and Blood Institute (NHLBI) asthma guidelines in 2020 for mild asthma. These groups no longer recommend short-acting beta-agonists (SABA) as monotherapy for mild (GINA) or mild-persistent (NHLBI) asthma. With the lag that can occur between guideline or evidence updates and changes in practice, this study sought to evaluate whether guideline adoption had occurred.

In this retrospective chart review, patient electronic medical records from a large healthcare system were evaluated from July 1 of 2021 to July 1 of 2022 to determine how many patients with mild asthma were prescribed as needed or daily inhaled corticosteroids (ICS) in addition to as needed SABA. The secondary outcome was to evaluate the incidence of exacerbations in patients with mild asthma, comparing those on guideline-directed therapy or not. In addition, we evaluated other patient factors increasing exacerbation risk in mild asthma.

For the primary outcome, of the 1,107 patients meeting inclusion criteria, 284 patients (26%) did not have documentation of guideline-directed therapy for mild asthma during the study period, while 823 (74%) were on guideline-directed therapy (Diff:48.7%; 95% CI:45.1 to 52.3%, p  < 0.001). For the secondary objective, 161 patients had an exacerbation (12% on guideline-directed therapy, 15.4% not on guideline-directed therapy). This difference in incidence of exacerbation between the two treatment groups was not statistically significant (Diff: -3.4%; 95% CI: -8 to 1.1%; p  = 0.133). In addition, being female, having GERD, and being obese were all statistically significant factors associated with having asthma exacerbations among our patient population.

Conclusions

Nearly one-fourth of patients with mild persistent asthma were not on guideline-directed therapy, despite updates in asthma guidelines (GINA 2019, NHLBI 2020). Factors such as being female, having GERD, and being obese were all statistically significant factors associated with having asthma exacerbations among patients with mild persistent asthma.

Asthma is a chronic respiratory disease characterized by airway inflammation, bronchial hyperresponsiveness, and reversible airflow obstruction [ 1 ]. Asthma is commonly classified as mild, moderate, or severe based on symptom frequency and severity, and these classifications guide treatment with the goals to reduce symptoms and prevent asthma exacerbations. The term mild asthma can be misleading, implying a low risk of serious disease sequelae. Because of this, some organizations have proposed no longer using the term mild to describe asthma [ 2 ]. According to the Centers for Disease Control (CDC), 25 million people in the United States are currently diagnosed with asthma, and a majority (50–75%) classified as having mild asthma [ 3 , 4 ]. Of those diagnosed with asthma, over 41% claimed to have one or more asthma exacerbations in a 12-month period, while nearly 2 million visited the emergency room due to uncontrolled asthma [ 3 ]. In addition, per a systematic review published in 2020, up to 22% of patients with mild asthma had a severe exacerbation in the previous year [ 5 ]. An earlier study published in 2007 found severe exacerbations in mild asthma represent 30–40% of asthma exacerbations requiring emergency consultation [ 6 ], highlighting the need for more effective treatment of mild asthma.

The Global Initiative for Asthma (GINA) and the National Heart Lung and Blood Institute (NHLBI) updated their asthma guidelines in 2019 and 2020, respectively. Both groups included a significant update to the recommended treatment of mild asthma, and the recommendation remains in the latest guideline updates. Before the 2019 GINA update, short-acting beta-agonist (SABA) monotherapy was considered appropriate only for step 1 therapy (mild intermittent asthma or very mild asthma). The fundamental change in the 2019 GINA guideline was the recognition that SABA monotherapy was no longer appropriate for any patient with asthma, regardless of severity classification. The 2020 NHLBI update continued to recommend SABA monotherapy for mild intermittent asthma, but no longer recommended it for mild persistent. Specifically, the use of daily inhaled corticosteroids (ICS) + as needed SABA, as needed ICS-long-acting beta agonist (LABA) or as needed ICS + as needed SABA are recommended over monotherapy with as needed SABA [ 2 , 7 ]. This change was prompted by evidence of ICS-containing treatment markedly reducing asthma hospitalizations, severe exacerbations, and death [ 8 , 9 , 10 ]. As these updates represent fundamental changes to the management of mild asthma, changes in prescribing patterns may lag behind guideline publication.

The purpose of this study was to evaluate how many patients with mild asthma were prescribed as needed or daily ICS in addition to as needed bronchodilator per the updated GINA and NHLBI guidelines. In addition, evaluation of incidence of exacerbations in patients with mild asthma, and examination of patient-specific factors that contribute to exacerbations, included but not limited to guideline-adherence, will also be assessed.

In this retrospective chart review, patient electronic medical records were evaluated from Banner Health, a large healthcare system with 30 hospitals and over 300 clinics across six states in the western part of the United States. This study was approved by Banner Health IRB. Charts were reviewed to determine how many patients with mild asthma were prescribed as needed or daily ICS in addition to as needed SABA. Charts were electronically reviewed from July 1, 2021, to July 1, 2022. Patients were included if they were a primary care patient age 12 years or older with an ICD-10 code(s) for mild or mild persistent asthma {ICD-10 codes: J45.30 (mild persistent asthma, uncomplicated), J45.31 (mild persistent asthma with (acute) exacerbation), J45.32 (Mild persistent asthma with status asthmaticus)}. A patient with a prescription, lab work, and/or encounter generated during study duration was considered an active patient. Patients were excluded if they were less than 12 years of age, had an active diagnosis for moderate persistent asthma or severe persistent asthma, an allergy to ICS-containing medications, or an active prescription for a nebulizer solution. The following data were collected: age, sex, race, payer type, active prescriptions for ICS, SABA, and ICS-LABA medications, prescriber, encounter diagnoses codes, location name, and date. The primary outcome was to evaluate how many patients with mild asthma were prescribed as needed or daily ICS in addition to as needed SABA. The secondary outcome was to evaluate the incidence of exacerbations {ICD-10 code: J45.901(unspecified asthma with (acute) exacerbation)} in patients with mild asthma, comparing those on guideline-directed therapy (daily ICS + as needed SABA, as needed ICS-LABA or as needed ICS + as needed SABA) or not (as needed SABA only). In addition to guideline-adherence, we evaluated other patient factors influencing exacerbation risk in mild asthma.

Statistical and data analysis

Categorical variables were reported as counts and percentages with differences between groups using chi-square, two-proportion, or Fisher’s exact test. Continuous measures were reported with means and standard deviation and/or, medians with interquartile ranges and differences between groups using student t-test. Lastly, a multivariate logistical regression was used to evaluate demographic and clinical characteristics most influencing asthma exacerbations. Minitab v20 was used for all statistical comparisons with alpha = 0.05.

Between July 1, 2021 and July 1, 2022, there were 1,107 patients who met inclusion criteria for this study. In evaluating the primary outcome, of those 1,107 patients, 284 patients (26%) did not have documentation of guideline-directed therapy for mild asthma during the study period, while 823 (74%) were on guideline-directed therapy (Diff:48.7%; 95% CI:45.1 to 52.3%, p  < 0.001). The mean age of those included in the study was 42.4 years for non-guideline-adherent patients and 43.7 years for guideline-adherent patients ( p  = 0.353) (Table  1 ). In addition, most of the population was female and Caucasian/white, with no statistical significance between the primary outcome groups ( p  = 0.781 and p  = 0.524, respectively) (Table  1 ). When examining provider type in respect to the primary objective (non-guideline-adherent versus guideline-adherent), 37% of patients seen in the primary care setting (primary care, family medicine and internal medicine clinics) have no documentation of guideline-directed therapy (Fig.  1 ).

Facility/provider type and guideline adherence

*Includes other specialty clinics with a small representation such as Obstetrics/Gynecology., Ophthalmology, Neurology, Urology, Dermatology, Gastrointestinal, etc

Looking at this graph we see provider type and whether or not the patient was on guideline therapy. It may be hard to attribute patients to just one facility because they could be going to 2–3 different providers listed here. The numbers here add up to over 2,500, which is well above our 1,107 patients in our inclusion group

When assessing the secondary objective, 161 patients of the 1107 had an exacerbation during the study period. Of patients not on guideline-directed therapy, 12% experienced an exacerbation. Of patients on guideline-directed therapy, 15.4% had an exacerbation. This difference in incidence of exacerbation between the two treatment groups was not statistically significant (Diff: -3.4%; 95% CI: -8 to 1.1%; p  = 0.133).

The multivariate logistical regression model (see Fig.  2 ) represents those demographic and clinical characteristics most influencing an asthma exacerbation ( p  < 0.001). As shown in the figure, asthma exacerbations decreased incrementally by 1.2% for each additional year of age ( p  = 0.006). Males were about 39% less likely to have an exacerbation when compared to females ( p  = 0.01). Those with gastroesophageal reflux disease (GERD) were 63% more likely to have an asthma exacerbation ( p  = 0.02). Obese patients were 73% more likely to have an asthma exacerbation ( p  = 0.01), while those with bronchitis being about 81% more likely to have an asthma exacerbation, but this was not statistically different ( p  = 0.082). Lastly, three characteristics trended towards increased incidence of exacerbation, but were not statistically significant; patients with documented guideline-directed therapy were 38% more likely to have an asthma exacerbation, with documented history of Covid were 47% more likely, and with bronchitis were 81% more likely ( p  = 0.124, p  = 0.183, and p  = 0.082 respectively). In conclusion, being female, having GERD, and being obese were all statistically significant factors associated with having asthma exacerbations among our patient population. Other factors that were assessed but did not fit the logistical regression model were COPD, pneumonia, influenza, allergic rhinitis or sinusitis, smoking, and heart failure.

Logistical regression model ( n  = 1107): Factors associated with at least one asthma exacerbation*

*Multivariate logistical regression including factors creating most parsimonious model. Overall model p  < 0.001, Concordance = 63.8%, R 2  = 3.57%, Hosmer-Lemeshow p  = 0.741

The results of this study indicate that about 3 in 4 (74%) patients with mild asthma did have documentation of guideline-directed therapy. Previously reported adherence rates to asthma guidelines have varied. A 2016 study assessed primary care adherence to the previous 2007 NHLBI asthma guidelines. This study found that 88% of patients had documented guideline adherence for reliever medication and 70.4% had guideline adherence to maintenance medication [ 11 ]. Data on adherence to the more recent guidelines is available from an international study that assessed adherence via provider and patient surveys. This 2021 study examined asthma therapy in four countries (Australia, Canada, China, and the Philippines) and found that 47% of patients were on guideline-directed therapy [ 12 ]. Our study found a greater percentage of patients on guideline-directed therapy (74% compared to 47%). This may be due to the increased amount of time from the updated guidelines release and/or data collection methodology.

Information in Fig.  1 allows an assessment of which facility had the greatest patient population not receiving guideline-directed therapy, which may help target providers with education on guideline updates. As shown in the results and in Fig.  1 , patients seen in the primary care setting (primary care, family medicine and internal medicine clinics) had the highest percentage of patients without guideline-directed therapy. This is valuable information as most patients with mild asthma will often be seen in a primary care setting due to the low severity of their asthma symptoms.

Regarding the secondary objective, patients in this study were found to be at a slightly greater risk for an asthma exacerbation if they were on guideline-directed therapy versus not; however, this objective was not statistically significant. The correlation of the timing of the asthma exacerbation and when the patient was started on guideline-directed therapy was unable to be determined based on the data gathered. During the study period, we assessed if the patient had an asthma exacerbation and if they were on guideline-directed therapy, but we did not assess the time at which these events occurred or in what order they occurred. In other words, during the study period, a patient who was not on guideline-directed therapy may have experienced an asthma exacerbation, and then was subsequently started on guideline-directed therapy. In addition, more acute or critical patients who were at a higher risk of having an asthma exacerbation may have been followed more closely by their practitioner which is why they were started on guideline-directed therapy sooner than other patients. Despite being followed more closely, they still had an asthma exacerbation due to being a higher risk patient. Finally, it is possible that some patients classified as having mild asthma actually have a more severe form of asthma and this may have contributed to the incidence of exacerbations.

Factors that were statistically significant with regards to exacerbation risk include female sex, GERD, and obesity. Previous studies have described morbidity and mortality risk factors for asthma, including high SABA use, increased age, ever smoking, and high blood eosinophils [ 13 ]. Few studies have specifically examined risk factors in patients characterized as having mild asthma. As discussed earlier, patients with mild asthma make up a large proportion of all patients with asthma, and these patients still experience exacerbations, but may not be treated with guideline-directed ICS therapy which is proven to reduce exacerbation risk [ 14 ]. Our study may add new insight into risk factors and treatment goals for patients with mild asthma, particularly optimizing treatment for GERD and obesity.

Limitations

Despite Banner Health having a large patient population, the number of patients meeting our inclusion criteria was low. This may be suggesting a low prevalence of mild persistent asthma, low documentation of patients as having mild asthma, or more severe patients because of the large influence of the academic facilities on excluded patients. The lower than expected number of patients in this study may have limited the results.

Additionally, a limitation to the study was our inability to correlate the timing of patient exacerbations and medication use. As a result, the number of patients on guideline-directed therapy who experienced an asthma exacerbation may have been falsely elevated.

Another limitation to this study was that it was difficult to determine which provider or facility was managing therapy because patients could have been visiting multiple facilities within the institution or even outside the institution. Lastly, we are unable to be certain that each patient had the correct diagnosis code entered on their problem list. This was an assumption that the provider diagnosed the patient correctly and updated their problem list accordingly.

Accurately assessing patients with mild asthma may be a limitation of this study, as patients with more severe disease may have been classified as having mild asthma due to underreporting of symptoms by patients or failure to recognize severity by providers, particularly primary care providers.

Finally, the number of asthma exacerbations experienced by each patient is unknown based on the data gathered. This study only characterized patients as having an exacerbation or not having an exacerbation during the study period. In addition to this, patients seen at an outside facility for asthma exacerbation treatment would not be accounted for in our electronic health record. Patient adherence to medication is something we cannot determine from this study but could have an impact on exacerbations.

Nearly one-fourth of patients with mild asthma in this study population were not on guideline-directed therapy, despite updates in asthma guidelines (GINA 2019 and NHLBI 2020). Factors such as being female, having GERD, and being obese are all statistically significant factors associated with having asthma exacerbations among patients with mild asthma. More work needs to be done to increase provider awareness regarding asthma guideline updates in outpatient and inpatient settings. Lastly, further studies in patients with mild asthma are needed to examine medication adherence, patient satisfaction, and exacerbation rate comparing patients on guideline-directed therapy versus those who are not.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Centers for Disease Control

Global Initiative for Asthma

National Heart Lung and Blood Institute

Short-Acting Beta-Agonists

Inhaled Corticosteroids

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Acknowledgements

We would like to thank the following pharmacists at Banner Health for their contributions to this project: Sophia Galloway, Virginia Boomershine, and Elizabeth Scheffel.

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BZ was involved in study design, literature search, data collection, data analysis, and manuscript preparation. JK was involved in study design, literature search, data collection, data analysis, and manuscript preparation. JG was involved in data collection and data analysis. All authors read and approved the final manuscript.

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Zerr, B.A., Kruse, J.M. & Glover, J.J. Evaluation of adherence to guideline-directed therapy and risk factors for exacerbation in mild asthma: a retrospective chart review. Allergy Asthma Clin Immunol 20 , 27 (2024). https://doi.org/10.1186/s13223-024-00888-6

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Asthma: Pathophysiology and Diagnosis

Susie yim yeh.

Harvard Program in Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 USA

Although asthma is a common disorder affecting approximately 7.8% of the United States population (Schiller et al. 2006) or 23 million Americans, the pathogenesis of this disease remains to be fully elucidated. Extensive research over the last few decades has yielded a better understanding of asthma. We know that the basic features of asthma include episodic airways inflammation, airways hyperresponsiveness, and mucous hypersecretion. Although we understand the basic clinical features of asthma, the links between symptoms, physical signs, and underlying pathophysiological mechanisms are still being delineated. Asthma is a heterogeneous disease process with varying phenotypes and presentations. In this chapter, we will briefly explore some major theories of asthma pathogenesis, both new and old. We will also explore how understanding the pathophysiology of asthma can help us to understand the symptoms and presentation of asthma, as well as the best strategies for diagnosing this disease.

Introduction

Although asthma is a common disorder affecting approximately 7.8% of the United States population (Schiller et al. 2006 ) or 23 million Americans, the pathogenesis of this disease remains to be fully elucidated. Extensive research over the last few decades has yielded a better understanding of asthma. We know that the basic features of asthma include episodic airways inflammation, airways hyperresponsiveness, and mucous hypersecretion. Although we understand the basic clinical features of asthma, the links between symptoms, physical signs, and underlying pathophysiological mechanisms are still being delineated. Asthma is a heterogeneous disease process with varying phenotypes and presentations. In this chapter, we will briefly explore some major theories of asthma pathogenesis, both new and old. We will also explore how understanding the pathophysiology of asthma can help us to understand the symptoms and presentation of asthma, as well as the best strategies for diagnosing this disease.

Pathology and Histology

What do the lungs look like in asthma.

The autopsies of patients who have died of asthma gave researchers the first clues as to the possible etiology of this disease. Although there have been many advances in the treatment of asthma, death from this airways disease is still an unfortunate outcome in a minority of patients. Before describing the abnormal features of the asthmatic airway, we must first briefly describe the basic features of the normal airway.

Asthma is thought to be a disease of the small airways. If one thinks of the lungs as a series of tubes that continues to divide, the tubes get smaller and smaller until they end in small air sacks (called alveoli), where the exchange of gas occurs. The characteristics of the larger tubes as compared to the smaller tubes are very different. In the lung, the larger tubes such as the trachea and main bronchus are supported by both cartilaginous rings and smooth muscle. However, as the tubes get smaller, these cartilaginous rings disappear and only a layer of smooth muscle remains (Fig. 2.1 ). These smaller tubes are called bronchi and bronchioles. Without the support of cartilage, when smooth muscle contracts, the airways become increasingly narrow. Smooth muscle surrounds other tubular structures in the human body, such as arteries, where smooth muscle contraction dictates the flow of blood to vital organs. Similarly, in the lungs, contraction of smooth muscle in the bronchioles determines the air flow. The cross-sectional area of all the bronchioles is much larger than the cross-sectional area of the biggest airway. Therefore, contraction of smooth muscle can greatly increase airway resistance and diminish the flow of air into the lungs by decreasing size of the small airways.

The basic structure of the respiratory bronchiole. The bronchiole differs from the larger airways in that it is surrounded only by smooth muscle without cartilage support. Also note the cells lining the airways consist of mucous secreting cells

The cells that line the respiratory tract are known as the respiratory epithelium . These cells vary in appearance and function. Some cells have hair-like structures (cilia), while other cells produce mucous. Beneath these cells lie connective tissue and more glands that secrete mucous. In the trachea, cartilage, and smooth muscle is present beneath these glands. As the airways become increasingly smaller, the amount of cartilage starts to decrease and smooth muscle becomes more prominent. In the smallest airways, such as the bronchioles, there is no longer any cartilage. The connective tissue and glands decrease and smooth muscle lies beneath the respiratory epithelium. There are also many small blood vessels that lie beneath the airway supplying nutrients to both the respiratory epithelium and smooth muscle cells. In asthma, these blood vessels can become leaky, allowing the infiltration of inflammatory cells and fluid, which can cause edema.

Asthma, at its core, is an inflammatory disease. In response to a variety of stimuli, some in the environment such as allergens, and some reflecting changes within the body as occurs with exercise, a cascade of reactions that we characterize as inflammation is triggered. Autopsies of patients with fatal asthma have shown many derangements consistent with inflammation in the structure of the airways. In addition, mucous plugs fill the airways. The cells that produce mucus appear larger and are more numerous than in patients without asthma. The bronchioles also appear edematous with an increased number of inflammatory cells (such as eosinophils, neutrophils, and mast cells) that infiltrate the airways. The connective tissue is thickened and the respiratory epithelium is denuded. In addition, the amount of smooth muscle that surrounds the airways is increased (Fig. 2.2 ); whether this is due to muscle contraction and hypertrophy or is another process secondary to inflammation is still up for debate. It was thought that these dramatic changes were specific to patients with fatal asthma; bronchoscopic biopsies of patients with mild asthma, however, have demonstrated some of the same features. Although these findings can be patchy, biopsies of patients with mild to moderate asthma have shown a significant amount of inflammation as demonstrated by denuded epithelium, thickened basement membrane, and infiltration of inflammatory cells including mast cells, lymphocytes, and eosinophils (Busse and Lemanske 2001 ).

Schematic of the respiratory bronchiole during an asthma attack. The airway is lined by the respiratory epithelium which is made of ciliated and mucous producing cells. These mucous producing cells increase mucous production. Mucous then plugs up the airway, making it harder for the asthmatic to breathe. Underneath the respiratory epithelium lies a layer of smooth muscle. When the smooth muscle contracts, the airway becomes smaller, decreasing airflow

Another hallmark of asthma is that it represents a potentially reversible disease process. Between asthma attacks or during mild attacks, the airways can appear normal (Barrios et al. 2006 ). If asthma continues to progress, however, these changes become more permanent. This process is termed airway remodeling , and is thought to be due to persistent airway inflammation (Holgate et al. 1999 ). Patients with airway remodeling have thickened airway walls, with an increase in the amount of tissue directly under the respiratory epithelium, and larger smooth muscle mass (Busse and Lemanske 2001 ). Once remodeling has occurred, the medications used to reverse obstruction of the airways become less effective and symptoms may be more chronic.

Pathogenesis

As mentioned earlier, the three basic features of asthma are airways inflammation, airways hyperresponsiveness, and mucous hypersecretion. These three features lead to bronchoconstriction and airflow obstruction, which manifest as wheezing and dyspnea in the patient with asthma. The challenge for most researchers has been to uncover triggers of airways inflammation in the patient with asthma. Several theories have emerged such as the TH2 hypothesis, the Hygiene hypothesis, the infectious causes hypothesis, and the Dutch hypothesis. What these theories have in common is that in the susceptible individual, there is an exuberant immune response after exposure to a substance whether it be an allergen, a virus, or something else. This increased immune response leads to airways inflammation and bronchoconstriction. Why this occurs is still debatable.

Allergy and the Immune System

Many researchers have tried to identify the main causes of airways inflammation. Abnormalities of the immune system, which protects our bodies from infection, have been thought to be major contributors to the development of asthma. More specifically, allergic responses have been considered to be the main determinants of the asthma phenotype. Extensive research over the years, however, has shown that there are different phenotypes of asthma and not all are mediated by allergies. Even so, we will first explore the allergy-driven TH2 hypothesis before describing some of the other theories of asthma pathogenesis.

The immune system is an intricate and complicated structure, the details of which are too complex to explore here. However, to understand asthma, one must have some understanding of how the immune system works. In order to fight infection, the human body has developed a complex system to identify foreign intruders and to “remember” them in case of further invasions. This is called the adaptive immune response . That way, the body can be ready immediately for the next attack. Yet to exist in this world, the immune system cannot recognize everything foreign as being dangerous or else we would not be able to smell flowers or eat food without coughing, sneezing, or developing fevers. Life would be unbearable. The immune system, therefore, has developed a way to distinguish between benign and malignant foreign particles or antigens . There are times, however, for unclear reasons, when the immune system recognizes benign antigens such as dust, animal dander, or food as being “dangerous.” When this occurs, we say that the person has an “allergy.” When the human body develops allergies, the bronchospasm, cough, and wheeze that develop is an exaggerated response to a benign particle.

What are the steps involved from being exposed to a piece of dust to developing wheezing? It is clear that this process does not happen to everyone and that only susceptible individuals have this problem. Over the last several decades there have been several basic immune mechanisms described including antibody-mediated and cell-mediated immunity, that are thought to be responsible for airways inflammation and obstruction in response to an allergic stimulus.

Antibody-Mediated Immunity

One of the most important immune cells is called the lymphocyte . These cells are the building blocks of the immune system. There are two types of lymphocytes, the B-cell and the T-cell . When activated, some B-cells differentiate into plasma cells which then produce antibodies that are released in the blood. When an antibody recognizes a foreign pathogen or antigen , the antibody attaches to the antigen and neutralizes it. In allergic diseases, a benign particle, or allergen , acts as an antigen. Another immune cell called the macrophage , then recognizes the antibody–antigen or antibody–allergen complex, absorbs the complex and destroys it. The human body makes several different types of antibodies that have slightly different functions. They are subdivided in to five classes of isotypes called IgA, IgM, IgG, IgD, and IgE. The antibody most important to asthma is the IgE isotype. IgE differs from the other isotypes in that instead of circulating freely in the blood and extracellular fluid, IgE is bound to mast cells . Mast cells reside in the airways and are loaded with enzymes that are released once the mast cell is stimulated by the IgE–allergen complex. In developing countries, the IgE-mediated immune response is important in fighting and killing parasites. However, in developed countries, IgE-mediated immune responses are most responsible for allergic reactions.

The immediate hypersensitivity response is IgE-mediated and is one of the most important causes of asthma. When IgE recognizes an antigen (or in this case allergen ), a cascade of events occur that cause the degranulation and release of toxic inflammatory molecules from these mast cells (including proteolytic enzymes and histamine), which were meant to destroy foreign intruders (Wills-Karp 1999 ). Even when no such intruders are present, these toxic molecules cause the airways to become inflamed. The toxic molecules attract more immune cells to the area, thereby worsening the inflammation. Blood vessels become engorged and leaky, thereby allowing cells to migrate out of the blood stream and into the tissues. In asthma, the mast cells attract white blood cells called eosinophils to the area. They also initiate the production of inflammatory chemicals, leukotrienes , that are important in asthma. Leukotrienes have been implicated in inducing airway hyperresponsiveness, eosinophilia, and mucous hypersecretion (Bochner and Busse 2005 ).

Asthmatics typically have two phases during an asthma attack, the early and late response. It is thought that when the allergen activates IgE and mast cells, the histamine, leukotrienes, and cytokines released cause immediate constriction of smooth muscles that can resolve in approximately 1 h. However, 4–6 h later, another bout of airways obstruction can occur. This late reaction is thought to be due to different cytokines that are being released by the mast cells, eosinophils, macrophages, and lymphocytes (Busse and Lemanske 2001 ). The late response is responsible for prolonged asthma attacks.

Cell-Mediated Immunity

The T-cell differs from B-cells in the kind of antigen to which they respond. B-cell antibodies identify whole molecules. T-cells, on the other hand, do not rely on antibodies but rather develop receptors that recognize small pieces of a molecule. This makes it easier to recognize and destroy very small particles such as viruses. T-cells also differ from B-cells in their diversity. There are several different types of T-cells called cytotoxic T-cells, type 1 helper T-cell (TH1 cells) and the type 2 helper T-cell (TH2 cells). The roles of all these different T-cell types are too involved to explain here. In general the TH1 and TH2 cells differ in the types of immune reactions that they promote. In asthma, the TH2 cells often recognize the same allergens as B-cell antibodies do and help to activate the B-cell. The cytokines that the TH2 cell secretes to “help” the B-cell often contribute to the development of airways inflammation in the patient with asthma.

The TH2 cell does not rely on IgE antibodies but instead recognizes the allergen directly through its own receptor. The TH2 cell then activates and releases the cytokines to attract and activate more immune cells. This process was discovered when it was recognized that antibody-deficient mice (who do not make IgE molecules) were able to develop asthma (Corry et al. 1998 ). In this scenario, when TH2 cells are activated, the release of cytokines act directly on airway smooth muscle to induce airway bronchospasm (Corry et al. 1998 ; Wills-Karp et al. 1998 ). These cytokines also increase mucous secretions, airway inflammation and eosinophilia in the same way that leukotrienes do, but through a different mechanism.

To further complicate matters, the cytokines (such as IL-4) released by the TH2 cells also contribute indirectly to the immediate hypersensitivity response. IL4 is a key player in mast cell maturation (Madden et al. 1991 ), IgE secretion (Finkelman et al. 1988 ) and eosinophil recruitment to the lung (Corry et al. 1998 ). These immune responses, therefore, potentiate each other, showing how asthma can be the result of several different simultaneous processes.

TH2 Hypothesis

The observation that TH1 and TH2 cells promote different types of immunity generated the idea that perhaps one type of immunity is dominant in a particular individual. Specifically, that in one person, the TH1 cell-mediated immunity could be more active than the TH2 cell-mediated immunity. Because TH2 cell-mediated immunity has been associated with allergen-induced inflammation, it was thought that individuals who had predominantly TH2 cell-mediated immunity would be more prone to asthma and allergy. This is the basis for the TH2 hypothesis.

Further research has suggested that TH1 and TH2 cells regulate each other. For example if the TH2 cell is more active, it will release chemicals to suppress the TH1 cell and vice versa. When tested in the lab, chemicals from TH1 cells were found to decrease production of TH2 cells (Scott 1991 ). The question then becomes, what determines which TH cell mediated immunity dominates in an individual?

Hygiene Hypothesis

As the TH2 hypothesis gained popularity, the idea that the environment may determine which TH response dominates in a particular individual began to emerge. Exposures to certain pathogens or allergens at a young age (or even during the neonatal period) could determine if a person would have a TH1 or a TH2-mediated immunity (Table 2.1 ). Furthermore, if a person had a predominantly TH2-mediated immunity, then that person would be more susceptible to allergic diseases and/or asthma. This hypothesis has been dubbed the “hygiene hypothesis.” However, the idea that immunity is either TH1 or TH2 mediated is too simplistic as evidence has shown there is a complicated interaction between these two that is still being explored. That being said, we will explore briefly the hygiene hypothesis and the rationale behind this intriguing idea.

Factors promoting TH1 and TH2 phenotype

Asthma is more common in Western countries (The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee 1998 ), suggesting there may be an environmental reason for the increased prevalence of the disease in these areas. The term “hygiene hypothesis” alludes to the idea that perhaps it is the decreased exposure to infections and allergens in the Western world that promotes TH2-mediated immunity. Furthermore, use of antibiotics has been associated with increased risk of asthma perhaps by decreasing exposure to infections that would promote the TH1 mediated immunity (Cohet et al. 2004 ; Droste et al. 2000 ). Interestingly, asthma is more prevalent in urban settings when compared to rural or farm settings (von Mutius 2000 ). Intense epidemiological research has looked at why this may be true. Several studies have looked at how exposure to endotoxin early in life could affect development of wheezing and asthma. Endotoxin, a component of (gram-negative) bacterial cell walls, can induce inflammation and cause bronchoconstriction when inhaled by asthmatics (Michel et al. 1989 ). Interestingly, endotoxin promotes TH1-mediated response and has been found to increase production of TH1-related cytokines (D’Andrea et al. 1992 ; Gereda et al. 2000 ; Lapa e Silva et al. 2000 ; Le et al. 1986 ). It appears that endotoxin is more abundant in farm settings, likely due to increased exposure to livestock, than in nonfarm settings (von Mutius et al. 2000 ). Although in decreased quantities, endotoxin can also be found in common household dust. Researchers have asked whether it is the exposure to endotoxin that predicts the development of asthma thereby explaining the differences in asthma prevalence between urban and rural/farm settings.

Litonjua et al. ( 2002 ) studied children from Boston, MA who were less than 5 years old. The results of this study, which was conducted over 4 years, showed that children who were exposed to higher endotoxin levels initially had increased wheezing during the first year of life. However, as the children became older, they had a progressive decline in wheezing. By age 5–9 years, children who had higher endotoxin exposure had less wheezing when compared to children who had lower endotoxin exposure. This paradoxical relationship whereby increased endotoxin exposure increases risk of wheezing early in life, but decreases risk of wheezing later in life, suggests that exposure to endotoxin may have “protective” effects. By enhancing TH1-mediated immunity, endotoxin exposure may decrease the development of asthma and/or allergy in susceptible individuals.

When studying other exposures that may enhance the TH1-mediated response it has been shown that previous exposure to Mycobacterium tuberculosis , hepatitis A, Toxoplasma gondii , Herpes Simplex 1 and the common cold have been associated with decreased risk of allergy or asthma. Viruses and bacteria activate cell-mediated immunity (TH1 response). The German Multicenter Allergy Study studied children from birth to 7 years of age and found that children who had more colds with a runny nose had less wheezing (Illi et al. 2001 ). Similarly, the Tucson Children’s Respiratory Study, which followed children from birth, found that children who had more siblings or attended daycare from an early age were more likely to have wheezing at age 2 but increasingly less likely to have asthma as they became older (at age 6, 8, 11, and 13) (Ball et al. 2000 ).

The hygiene hypothesis, however, has remained very controversial. As stated earlier, the simple TH1 versus TH2 model does not hold true in many instances. For example, in rural Africa where parasitic diseases are common, infection with certain parasites ( Shistosoma species) (van den Biggelaar et al. 2000 ) and Ascaris hook-worm (Scrivener et al. 2001 ) was associated with decreased prevalence of asthma and allergy. Parasitic diseases activate the TH2 response and require IgE to fight off these infections. Therefore, one might think that factors favoring the TH2 phenotype would increase the incidence of asthma and allergy. However, on closer inspection, it is thought that another factor may be “bypassing” the TH2 response in parasitic diseases. Another group of T-cells called regulatory T-cells that produce a cytokine called Interleukin-10 (IL-10), may be increasingly active during parasitic infections. It is thought that these regulatory T-cells can override the TH2 response. In a mouse experiment, injection with IL-10 producing T-cells decreased the allergic response in these animals (Cottrez et al. 2000 ). In other experiments, IL-10 in combination with IL-4 caused B lymphocytes to produce IgG instead of IgE (Jeannin et al. 1998 ). This line of research is promising in further clarifying the immune responses that are contributing to the asthma and allergy phenotype.

Lastly, the hygiene hypothesis does not explain the cause-effect relationships that occur later in life. In other words, once an individual has established an allergic response, repeated exposures do not decrease this response. In the endotoxin example, individuals with established asthma have increased airways inflammation, bronchoconstriction, and susceptibility to viral illnesses when exposed to endotoxin (Reed and Milton 2001 ). Endotoxin exposure is a common cause of asthma in the workplace and repeated exposures in asthmatic individuals leads to chronic bronchitis and emphysema (Reed and Milton 2001 ). Instead of mitigating the allergic reaction, repeated exposures to endotoxin in the person who already has asthma causes worsening disease. This example suggests that the hygiene hypothesis may only be relevant early in life and cannot be extrapolated to the adult setting.

Viral/Bacterial Infections

Since the 1970s there has been a well-established relationship between asthma and respiratory tract infections (Blasi et al. 2001 ). Many patients with asthma have worsening of their symptoms in the setting of a respiratory infection. In children, studies have shown up to 45% of asthma exacerbations are related to respiratory infections (Mertsola et al. 1991 ). Likewise, in adults, up to 37% of asthma exacerbations were associated with respiratory infections (Teichtahl et al. 1997 ). However, whether these infections are involved in the etiology of asthma or the progression of disease has remained unclear. There is also interest in whether respiratory infections play a significant role in the TH1/TH2 or hygiene hypotheses as well. Although more commonly associated with viruses, several specific bacteria such as Chlamydia pneumoniae and Mycoplasma pneumoniae have been increasingly associated with asthma.

C. pneumoniae and M. pneumoniae are two common bacterial respiratory infections and are typically associated with pneumonia. C. pneumoniae is different from most other bacteria in that it must invade cells, such as respiratory epithelial cells and macrophages, in order to replicate. However, because C. pneumoniae does not have to destroy the cell that it invades; it can persist as a latent infection by allowing infected cells to proliferate. Latent infections can be quiescent without causing symptoms. If triggered, however, they can erupt into an acute infection. Cold sores, for example, are due to latent infection with Herpes Simplex virus that develops into an acute infection from time to time. C. pneumoniae has been implicated in acute exacerbations of asthma (Allegra et al. 1994 ) and chronic asthma (Black et al. 2000 ).

C. pneumoniae has been associated with asthma since the 1970s. Since then, efforts to quantify this association have been attempted. Several studies have measured antibodies against C. pneumoniae in the blood of asthma patients and found an increase in certain types of antibodies (IgA) to C. pneumoniae when compared to controls (Berkovich et al. 1970 ; Gencay et al. 2001 ; Huhti et al. 1974 ). Antibody studies, however, are difficult to interpret since the presence of antibodies does not confirm whether an infection is past, latent, or acute. It has been suggested that chronic infection with C. pneumoniae is more prevalent in asthmatics (Biscione et al. 2004 ; Gencay et al. 2001 ). When using methods to directly test for presence of the bacteria in nasal aspirates of asthmatics and their non-asthmatic spouses over a 2 month period, it was found that 22% of the asthmatics and 9% of the spouses had presence of the organism at least once during the study period (Biscione et al. 2004 ). However, it was still unclear as to whether the increase in positive tests for C. pneumoniae in asthmatics truly represents active infection or colonization.

It is logical to ask that if C. pneumoniae infection is associated with asthma, then does treatment with antibiotics improve symptoms and outcome? Unfortunately the results have been mixed. Several studies have shown that treatment of asthmatics with antibiotics for 6–8 weeks have shown decreases in eosinophil counts (Amayasu et al. 2000 ) and improvements in peak expiratory flows (PEF) (Black et al. 2001 ) but that the effect on pulmonary function tests were modest at best. Most recently, a double-blinded, randomized, placebo-controlled trial attempted to more accurately assess the effect of antibiotics (against C. pneumoniae and M. pneumoniae ) in the setting of an acute asthma exacerbation (Johnston et al. 2006 ). Patients with an acute asthma exacerbation were randomized to take placebo or an antibiotic for 10 days in addition to regular asthma treatment. Although asthma symptoms improved in the antibiotic group, there was no difference in PEF. Interestingly, 61% of the subjects studied had evidence of infection from either C. pneumoniae or M. pneumoniae or both but unfortunately there was no correlation between antibiotic response and history of infection in this study.

Results have been similar with M. pneumoniae , a common bacteria responsible for “atypical” or “walking” pneumonia. Like C. pneumoniae , it has been implicated in the etiology, progression, and clinical course of asthma, but treatment with antibiotics has not yielded significant improvements. It is the smallest free-living organism and is different from other bacteria in that it does not have a cell wall. It infects the respiratory epithelium and disables the ciliated cells responsible for clearing mucus and foreign particles from the airways. Like C. pneumoniae , M pneumoniae can persist as a chronic infection. Although it does not enter cells like C. pneumoniae , it can burrow between cells, evading host defenses and establishing residence in the airways.

Despite unclear results in small clinical trials assessing the effectiveness of treatment with antibiotics in asthmatics, there is still much interest in what role these bacterial infections play in the development of asthma. As discussed earlier, the hygiene hypothesis suggests that exposures to certain infections early in life may induce a TH1-mediated immunity resulting in a decreased propensity for asthma. However, once the allergic phenotype is established, recurrent exposures to a pathogen or allergen exacerbates the disease. Researchers looked at this phenomenon in an allergic-asthma mouse model. Chu and colleagues exposed mice to M. pneumoniae at different times and observed the response (Chu et al. 2003 ). When they infected the mice before exposure to an allergen, the mice had significantly less bronchial hyperresponsiveness, and lung inflammation and had increased production of cytokines associated with the TH1 response. Conversely, when they infected the mice after exposure to an allergen, they developed increased bronchial hyperresponsiveness, and lung inflammation, and produced cytokines associated with the TH2 response (IL-4). This line of research is very interesting and suggests that both C. pneumoniae and M. pneumoniae may have varying importance in the development and progression of asthma based on when the infection occurs.

Although we have been discussing the role of bacterial infections in asthma pathogenesis, viral infections have been implicated in the etiology of asthma as well. Viral infections during infancy have been associated with the development of asthma. This has been most convincing in studies of Respiratory Syncytial Virus (RSV). Most children are infected with RSV by 2 years of age (Simoes 1999 ) and many are hospitalized. RSV can cause respiratory distress, wheezing, and fever. It can cause a “bronchiolitis,” inflammation of the respiratory bronchioles described earlier. Many have observed that children who suffered from RSV bronchiolitis as an infant had a higher propensity to wheeze for years after the infection (Stein et al. 1999 ). Sigurs and colleagues (2005) studied a group of children who were hospitalized with RSV bronchiolitis as infants (<1 year old). They compared this group, which was followed until age 13, to a group of children who had never been hospitalized with RSV bronchiolitis. These researchers found that children in the RSV group had increased wheezing and airways obstruction. What was also interesting was that these children had increased allergies to common inhaled allergens. This research suggests there may be a relationship between early RSV infection and the development of asthma and allergies later on in life. However, other studies have shown that infants infected with RSV “outgrew” their wheezing and did not go on to develop asthma in adolescence (Taussig et al. 2003 ). Whether RSV is merely a risk factor for asthma or is a causative agent in asthma pathogenesis remains unclear.

In addition to being implicated in asthma pathogenesis, viral infections are commonly associated with asthma exacerbations (Venarske et al. 2006 ). Often, when a person develops an asthma attack, there is usually an inciting factor or “trigger” associated with the attack. For many asthmatics, the common cold can precipitate an attack. In fact, viruses have been associated with up to 85% of asthma exacerbations in children (Johnston et al. 1995 ) and 60% of exacerbations in adults (Nicholson et al. 1993 ). It has been shown that during times when viral syndromes are “going around” there are increased admissions to area hospitals with asthma exacerbations (Johnston et al. 1996 ).

The reason why upper respiratory viruses have been associated with asthma exacerbations, however, has remained unclear. Rhinovirus , one of the viruses responsible for the common cold, has been most frequently associated with asthma exacerbations. One study found that infection with rhinovirus was associated with an increase in asthma-related hospitalizations (Venarske et al. 2006 ). Some have suggested that viruses may potentiate the inflammatory response to allergens causing bronchospasm and airways obstruction in asthma patients (Busse and Lemanske 2001 ; Calhoun et al. 1991 ). Others have proposed that asthma may cause abnormalities in the immune system that makes it harder to fight viral infections in the airway (Papi and Johnston 1999 ). The role of rhinovirus and other viral illnesses (such as influenza, parainfluenza, and coronavirus ) in causing or contributing to asthma exacerbations needs to be further clarified.

Dutch Hypothesis

Before delving into what the Dutch Hypothesis is, we must first briefly explain the differences between asthma and chronic obstructive pulmonary disease (COPD). As we have been discussing, asthma is characterized by reversible airflow obstruction, airways hyperresponsiveness, and increased mucous secretion. Typically, asthma does not cause progressive loss of lung function and the lung parenchyma itself remains intact. Usually, asthma presents in childhood or young adulthood. On the other hand, COPD, a term used to describe chronic bronchitis, emphysema, and a variety of less common conditions such as bronchiectasis, is commonly associated with smoking and presents in older adulthood. Even though COPD is also characterized by airflow obstruction, it is usually irreversible or only partially reversible. There is also progressive loss of lung function. Asthma and COPD are commonly thought of as distinctly different diseases. Asthma has been described as an inflammatory airway disease mediated by a dysregulated immune response (as described by the TH2 hypothesis). COPD, on the other hand, is thought to occur when destructive enzymes damage the lung in response to some inflammatory stimulus (i.e., cigarette smoke).

The Dutch Hypothesis was first proposed in the 1960s and is one of the older but still relevant theories on asthma/COPD pathogenesis. During that time, tuberculosis was the most common respiratory illness but as effective treatment for tuberculosis became available, Drs. Orie and Sluiter began to notice that obstructive lung diseases were very common with similar characteristics in both younger and older patients (Postma and Boezen 2004 ). They proposed, in the first Bronchitis Symposium held in Groningen, Netherlands, that obstructive airways diseases such as asthma, chronic bronchitis, and emphysema should be considered not as different diseases but as different manifestations of one disease entity, which they called chronic nonspecific lung disease (CNSLD) (Postma and Boezen 2004 ). They hypothesized that both genetic and environmental factors contribute to the pathogenesis of CNSLD and that it is the interaction between these two that determines what phenotype a person will develop. One example of an interaction between a person and his/her environment is smoking. Tobacco smoke has been highly associated with COPD. However, only 10% of smokers get COPD suggesting that there is a genetic propensity for a person to develop COPD in response to cigarette smoke. There has also been an association between passive smoke exposure and the development of asthma in children. According to the Dutch hypothesis, the time of tobacco smoke exposure, whether in childhood or adulthood, and the type of exposure, passive or active, determines if a person with genetic susceptibility develops the asthma or COPD phenotype.

The Dutch hypothesis, as it is now known as, has been controversial. Efforts to try and test this hypothesis have been flawed as study designs do not lend to testing a process that spans a lifetime. Also, current studies of asthma and COPD have had strict inclusion criteria that try to eliminate subjects who have aspects of both, which limits our ability to determine if the pathogenesis of the two is similar. Over the years, however, there has been some evidence to support the Dutch hypothesis. Clinically, there are populations of asthma patients who have loss of lung function similar to COPD (Jeffery 2000 ; Ulrik et al. 1995 ). Similarly, there are patients with COPD who have reversible airflow obstruction (Bousquet et al. 1996 ). These observations suggest that there is considerable overlap between asthma and COPD.

Other observations have contributed to the blurring between asthma and COPD. There is evidence to suggest that both conditions are secondary to lung inflammation. In the past, different types of inflammation were described in patients with asthma and COPD. In asthma, it was thought that the inflammatory process was confined to the airway and that in COPD, the inflammatory process was confined to the lung parenchyma. However, there have been some studies that have shown that there are inflammatory cells, such as eosinophils and neutrophils, within the lung tissue in some subjects with asthma (Kraft et al. 1996 ; Wenzel et al. 1999 ). Additionally, biopsies of COPD subjects have shown high numbers of eosinophils in the airways especially during acute exacerbations (Saetta et al. 1994 ). Asthma and COPD share histologic features suggesting that there is substantial overlap between these two disease processes.

There have been several other features of both diseases that suggest a common pathogenesis. For example, the airways of asthma and COPD patients are similar. Both have an increase in mucous secreting cells lining the airways. Increases in smooth muscle surround the airways, however, was thought to be unique to asthma. Recent studies have shown that there is also an increase in smooth muscle among COPD patients as well (Jeffery 2000 ). Finally, changes in the lung parenchyma itself have shown some similarity among asthma and COPD subjects. Typically, as already mentioned, asthma is thought to be strictly an airways disease that does not affect the lung parenchyma or alveoli. However, the destructive enzymes found in COPD lungs have also been found in biopsies of asthma lungs as well (Atkinson and Senior 2003 ; Bousquet et al. 1996 ).

Studies are ongoing to further assess whether asthma and COPD are two distinct diseases or different presentations of the same disease. Over the years, the popularity of the Dutch Hypothesis has waxed and waned. However, there has been growing scientific evidence to support this hypothesis, which highlights that asthma is indeed a complex and heterogeneous disease process.

Asthma Subtypes

Although the majority of asthma is initially triggered by allergies, there are several different phenotypes of asthma that have different characteristics from the common allergy-induced asthma. “Intrinsic asthma,” aspirin-induced asthma (AIA), and exercise-induced asthma (EIA) are a few asthma subtypes that have unique characteristics not readily associated with allergens. There are, however, several other subtypes of asthma, such as gastroesophageal reflux associated asthma, obesity-related asthma, menstrual cycle-related asthma, and nocturnal asthma that are also included in the asthma syndromes, but will not be discussed here.

Intrinsic Asthma

The term “intrinsic asthma” has been used to describe patients who suffer from asthma but do not have typical features of atopy or allergies. This is in contrast to the allergy-induced (“extrinsic”) asthma we have been discussing. Patients with “intrinsic” asthma do not have allergies, family histories of atopy, abnormal serum IgE levels, or hypersensitivity reactions to skin prick-tests. The clinical course of patients with intrinsic asthma differs as well. Usually, patients with intrinsic asthma tend to be older, have later onset of asthma, and more severe disease (Ulrik et al. 1995 ). For many years, it was believed that “intrinsic” asthma represented a different pathological process leading to asthma and that the distinction between “intrinsic” and “extrinsic” (allergy-induced) asthma was very apparent. More recently, however, the differences between “intrinsic” and “extrinsic” asthma have become less clear. In one study, lung biopsies of patients with extrinsic asthma were compared to patients with intrinsic asthma (Humbert et al. 1996 ). Both had similar inflammatory cells and cytokines present, suggesting that a similar process was occurring in both forms of asthma regardless of whether the patient had allergies or not. These findings have prompted researchers to view “intrinsic” asthma differently. Instead of thinking of “intrinsic” asthma as being different from “extrinsic” asthma, there may only be differences in the triggers leading to the same causative pathways for asthma (Humbert et al. 1999 ). For example, some have suggested that intrinsic asthma may be a form of autoimmunity, triggered by a respiratory viral illness. In other words, antibodies made to the initial viral illness may now be initiating a cascade of inflammation leading to asthma (Humbert et al. 1999 ). Others believe that patients with “intrinsic” asthma are actually allergic to something that researchers have not yet been able to identify (Humbert et al. 1999 ). The pathogenesis of “intrinsic” asthma has not been elucidated and may reflect a heterogeneous process rather than a single disease entity. Although similarities between “intrinsic” and “extrinsic” asthma exist, the concept that asthma does not necessarily represent a solely allergy-related disease is important and speaks to the complexity of asthma.

Aspirin-Induced Asthma

One could consider AIA a kind of “intrinsic” asthma for which we know the trigger. Aspirin is one of the most widely taken medications in the world. In the United States alone, over 80 billion tablets per year are consumed. As such, the recognition of AIA is important as AIA may represent 10–20% of the asthma population (Sturtevant 1999 ). The AIA syndrome usually includes a triad of symptoms: nasal polyps and nasal congestion, sinusitis, and asthma with chronic symptoms. Patients with AIA often have chronic severe asthma with acute symptoms triggered after ingestion of aspirin or a similar drug (such as ibuprofen). Many times, symptoms can begin within 3 h after ingestion of aspirin with a profuse runny nose, swollen eyes, and flushing of the face in addition to wheezing. Breathing can become severely impaired, requiring hospitalization, and can progress to respiratory failure.

Although symptoms begin shortly after exposure to aspirin, AIA is not an allergic reaction per se. Skin prick tests with aspirin are usually negative, indicating that an antibody to aspirin does not exist in patients with AIA (Babu and Salvi 2000 ). Instead, aspirin blocks enzymes and, by doing so, causes increased production of cytokines called leukotrienes. These leukotrienes, in turn, promote inflammation and asthma in the susceptible individual. AIA is an example of how different mechanisms can lead to asthma.

Exercise-Induced Asthma

Like AIA, EIA is also not allergen mediated. It is very common with reports of 40–90% of asthmatics affected (Bundgaard 1981 ; Tan and Spector 2002 ). Many asthmatics experience increased airways resistance during exercise. Because of the dyspnea experienced during exercise, many patients with asthma often do not pursue aerobic activities as much as their non-asthmatic counterparts and are less fit as a result (Garfinkel et al. 1992 ). EIA, therefore, is important to recognize and treat so that patients with asthma can become more involved in exercise. Patients with asthma often feel better when they are physically fit (Ram et al. 2005 ). It is also thought that EIA may be triggered by moving large amounts of air in and out of the lungs. If asthmatics are more fit, they may breathe less heavily with mild to moderate exercise thereby decreasing the triggers for EIA (Ram et al. 2005 ).

The mechanism for EIA is debated. Two of the most common theories are the osmotic hypothesis and the thermal hypothesis . The thermal hypothesis suggests that bronchoconstriction during exercise is due to changes in temperature and water content of the airways (McFadden and Gilbert 1994 ). As large volumes of air move in and out of the lungs, the airways warm and humidify that air (also known as conditioning). Although the airways warm and heat air continuously (regardless of whether we are exercising or not) when we are quietly breathing with low tidal volumes, only a portion of the airways heat and humidify the air. During exercise, however, ventilation can increase by a factor of 20. As ventilation increases, the conditioning of air moves from the upper airways to the lower airways where more movement of heat and water from the airway cells is required to heat and humidify the air (McFadden and Gilbert 1994 ). When exercise stops and ventilation decreases, the airways rewarm quickly as they are no longer losing heat and water to the air. This cycle of cooling and rewarming is associated with airway narrowing and bronchoconstriction. Breathing warm humidified air ameliorates exercise-induced bronchoconstriction and breathing cold dry air worsens it (Bundgaard et al. 1982 ). It is not entirely clear why the airways narrow in response to rapid cooling and rewarming although increased blood flow and subsequent airway edema is thought to play a role (McFadden and Gilbert 1994 ; McFadden et al. 1986 ).

The osmotic hypothesis, on the other hand, suggests that airway dehydration during exercise causes a series of events leading to airway smooth muscle contraction and increased airways resistance (Anderson 1984 ). Proponents of the osmotic hypothesis argue that it is water loss, not changes in temperature that lead to bronchoconstriction. During exercise, large volumes of air move in and out of the lungs as respiratory rate and tidal volume increase. This movement of air is thought to cause evaporation of water in the airways. It is thought that the water loss causes an increase in osmolarity, which then triggers cells to release inflammatory chemicals, which in turn act on smooth muscle to contract. The loss of water in the lungs is also thought to cause an increase in blood flow to the lungs that can cause edema of the airways and even worsening airway constriction (Anderson and Daviskas 2000 ). Observations that EIA occurs when subjects breath gases of varying temperature but similar water content supports the osmotic hypothesis (Ingenito et al. 1988 ). Treatment of EIA usually consists of using a bronchodilator before exercise

Until now, we have discussed the pathogenesis of asthma and possible mechanisms for increased airways inflammation. This inflammation in turn leads to air flow obstruction and airway hyperresponsiveness. But what does this mean in terms of how asthma manifests clinically? How does this lead to symptoms of shortness of breath? What happens to respiratory physiology when asthma occurs?

The hallmark of asthma is reversible airways obstruction. As the airways become narrowed during an asthma attack, resistance of the airways increases and airflow into the lungs is diminished at the same level of respiratory effort. One could imagine this by comparing the difference between blowing into a large straw versus a small straw. If one blows the same volume of air through the large and small straw, it will take a significantly longer time to blow out all the air through the small straw because flow is greatly diminished. The lungs are more complex than the one straw system, however, as smaller and smaller branching airways have differing lengths, compliances, and different types of air flow (laminar and turbulent). Because of this, there comes a point when no matter how hard one blows, flow will not increase. This is called airflow limitation.

One of the most common complaints in patients with asthma is that they have difficulty breathing in. There are several reasons for this. With increased bronchoconstriction there is diminished air flow and increased airways resistance. In order to compensate for the increase in airways resistance, the inspiratory muscles must generate greater tension. Imagine that instead of blowing through the small straw, that one tries to breathe in through the small straw. The amount of effort required to take in a breath will increase. However, it turns out that the increased work of breathing associated with inhalation is complicated by a second factor, hyperinflation of the lungs and chest wall. Furthermore, inhalation is an active process; muscle activity is required. Exhalation, on the other hand, is typically passive during quiet breathing. The normal elastic properties of the lungs and chest wall push air out of the lungs during exhalation.

Now imagine trying to blow out through the small straw and then continue to breathe in and out through this small straw. Although one may not be aware of it, as one continues to breathe in and out through that small straw, a process called “dynamic hyperinflation” is occurring. In other words, because it takes longer to exhale out all the air when air flow is decreased, one may initiate the next breath before all the air is exhaled from the last breath. The volume of the lung and chest wall then increases. The next breath is even harder to take in because at higher lung volumes, the inspiratory muscles operate at a shorter length and are less able to generate tension. In addition, the compliance of the lungs and chest wall is reduced at higher lung volumes. This means that the respiratory system is stiffer and more work is required to take in a breath. You can try to experience this by taking a breath in before you have fully exhaled the last breath. When a group of patients with mild asthma were given medication to induce bronchoconstriction, hyperinflation was the greatest indicator of how short of breath they felt (Lougheed et al. 1993 ). Surprisingly, an increase in airways resistance did not correlate with how dyspneic the subjects felt. This points to the importance of hyperinflation as a cause of dyspnea in the asthmatic patient.

Hyperinflation can also induce “length-tension inappropriateness” another mechanism that may contribute to dyspnea in asthma. If tension is generated in the muscle but it does not shorten appropriately because of the mechanical load on the system (similar to when trying to lift a weight that is too heavy), there is a discrepancy between the tension generated in the muscle and the degree to which it shortens (Campbell and Howell 1963 ). This concept has been broadened to include discrepancies between the neurological output to the muscles and the mechanical response of the respiratory system (neuromechanical dissociation). If the inspiratory muscle force generated does not match the expected change in lung volume, feelings of breathlessness may occur (Campbell and Howell 1963 ). Hyperinflation contributes to neuromechanical dissociation in several ways. The hyperinflated lung places the respiratory muscles at a mechanical disadvantage making these muscles less effective in creating tension. Therefore, even though the brain is sending out a message to the respiratory muscles to contract, the force generated and the change in lung volume may not match what the brain expects, causing neuromechanical dissociation. Hyperinflation also creates an inspiratory load that the respiratory muscles have to overcome before flow into the lungs can occur. This phenomenon is called “auto PEEP” or positive end expiratory pressure. What this means is that if the lungs have residual air in them because one could not fully exhale, there is still positive pressure in the lungs at the end of the breath. Normally, exhalation is a passive process akin to letting air out of a balloon. When we exhale, the pressure in our lungs equilibrates to atmospheric pressure. If one does not fully exhale, however, there may be a few centimeters of H 2 O pressure left in the lungs before inhalation begins. The flow of air travels from areas of low pressure to high pressure. In auto PEEP, the inspiratory respiratory muscles must first overcome this pressure gradient to equilibrate to atmospheric pressure, and only after that can negative pressure be generated so that air can flow into the lungs. Thus, there is a period of time when the respiratory muscles are firing but no air is flowing into the lungs and, therefore, there is no change in lung volume. Imagine walking about while breathing through a mouthpiece that is connected to a valve that does not open until you generate a negative pressure of 5 or 7 cm H 2 O with your inspiratory muscles. It is not surprising that individuals with auto-PEEP complain of shortness of breath.

However, there are many patients with mild asthma who complain of chest tightness or difficulty breathing with only mild bronchoconstriction, levels of airways obstruction not associated with hyperinflation. These symptoms cannot be readily explained by increased work of breathing alone. Several studies have elucidated what may be occurring in this groups of patients. Taguchi et al. ( 1991 ) tested subjects by having them inhale a medication that causes bronchoconstriction and compared the respiratory sensation associated with an asthma-type reaction in the lungs to what the subjects felt when breathing through a high resistance (like our straw example). Although the degree of hyperinflation was the same in both conditions, subjects felt more short of breath when they were given a medication that caused bronchoconstriction. This sensation of shortness of breath was relieved when the subjects breathed in lidocaine (a topical anesthetic). This study suggests that there are nerve receptors in the lungs that contribute to the sensation of breathlessness during bronchoconstriction. Binks et al. ( 2002 ) tried to clarify further the mechanism behind the chest “tightness” often described by asthmatics during an attack. They gave patients inhaled medication to provoke bronchoconstriction. They then placed these patients on a mechanical ventilator thereby eliminating the effort required by the patient to inhale by having a machine breathe for them. Even though the patients felt like it required less effort to breathe on the ventilator, they still experienced the sensation of chest tightness. They then put subjects without bronchoconstriction on a mechanical ventilator and increased the end expiratory volume to mimic hyperinflation. Even though their lungs were hyperinflated, the subjects did not experience chest tightness. This experiment suggests that the feeling of chest tightness is separate from the effort of breathing during an asthma attack. Although the effort to breathe is related to bronchoconstriction and the resultant increased work of breathing, tightness may be caused by changes within the airway itself that lead to stimulation of pulmonary receptors, which may send messages to the brain creating the sensation of tightness.

Bronchoconstriction may also affect the delivery of oxygen into the lungs. If airflow to the lungs is diminished, it is hard to get air in and out and, therefore, the movement of oxygen into the lungs and carbon dioxide out of the lungs is impaired. The human body, however, has developed an interesting system to deal with changes in airflow and oxygen delivery to the lungs. The body has a tremendous ability to constrict blood flow to areas of the lung that have low oxygen levels. This phenomenon is called hypoxic vasoconstriction. In response to low oxygen levels in the lungs, the body will decrease flow of blood to these areas and divert blood to areas of the lung with normal oxygen levels. Because asthma is a heterogeneous disease process, some areas of the lung will experience inflammation and bronchoconstriction while other areas of the lung will be relatively normal. Therefore, the body usually can maintain adequate oxygen levels even in the face of mild to moderate asthma attacks.

Another mechanism that contributes to near normal oxygen levels during an asthma attack is hyperventilation. During a mild or moderate asthma attack, the patient will typically hyperventilate. Possible reasons for hyperventilation include stimulation of pulmonary receptors as well as behavioral factors (shortness of breath and anxiety can lead to hyperventilation). The rapid replacement of oxygen in the alveoli during hyperventilation helps to maintain normal oxygen levels in the blood.

In patients with fatal or near-fatal asthma, however, hypoxemia may blunt the sensation of dyspnea or uncomfortable breathing, making it more difficult for individuals to recognize the severity of their problem, thereby leading to a delay in seeking medical treatment. Although hypoxemia is not a common feature of asthma, the body’s attempts to divert blood to normal lung is insufficient when bronchoconstriction becomes severe. If there is little normal lung to which to divert blood, oxygen levels will start to decrease. In people without asthma (Chronos et al. 1988 ), or with other lung diseases such as COPD (Lane et al. 1987 ), hypoxemia itself can provoke shortness of breath. Unfortunately, when patients with asthma become hypoxemic, the ability to feel short of breath or chest tightness may diminish (Eckert et al. 2004 ).

Just as the pathogenesis of asthma is relatively complex, the signs and symptoms of asthma can be confusing as well. Asthma can present with a paucity or overabundance of symptoms, and can coexist with other illnesses. There are also many disease processes that can mimic asthma, thereby confusing health care providers. Finally, because asthma is an episodic disease, patients can have normal exams and pulmonary function tests between “attacks,” which makes diagnostic studies insensitive to the presence of asthma. According to the National Heart Lung and Blood Institute, the diagnosis of asthma should be considered in anyone who has episodic airways obstruction, reversible (or at least partially reversible) airways obstruction, and in whom other diagnoses have been excluded (Teichtahl et al. 1997 ). We will review the presenting symptoms of asthma, the role of diagnostic studies (such as pulmonary function tests, peak flow, and methacholine challenge tests (MCT)) and the conditions that may mimic asthma and which should be considered in difficult cases.

Many patients with asthma will initially present with wheezing, a high pitched sound usually heard during exhalation. As the airways narrow and airways resistance increases, there is more turbulent flow causing vibrations that we hear as a “wheeze.” Some have argued that the opening and closing of airways also contributes to this vibration. However, a lack of wheezing does not exclude the diagnosis of asthma. First, because asthma is an episodic disease, wheezing is not always present; patients who present to their health care provider during an asymptomatic period can have a completely normal exam. Second, the sound of wheezing actually decreases if airways resistance becomes severe. If airways resistance becomes so high that air flow is severely reduced, as in cases of extreme bronchoconstriction, turbulent flow can no longer be heard. Therefore, a patient who presents with a severe asthma attack can initially have wheezing that subsequently quiets down or stops. Instead of interpreting the lack of wheezing as an improvement in asthma, one must be vigilant that this does not signify a worsening of airways obstruction. Similarly, complete absence in breath sounds, or a “quiet chest” can also signify worsening airways obstruction and impending respiratory failure.

Some patients never develop wheezing as a symptom of asthma. There are many patients whose initial symptom is cough. This phenomenon has been termed “cough-variant” asthma. Gastroesophageal reflux disease (GERD), postnasal drip, and asthma are the three most common causes of chronic cough (Irwin et al. 1990 ). Because asthma is so common in the diagnosis of chronic cough, empiric treatment with bronchodilators (beta-agonists, which cause smooth muscle relaxation) is a common diagnostic test to evaluate if asthma is the cause of chronic cough. However, there is complex relationship between GERD and asthma. Acid reflux can cause bronchoconstriction through a neural reflex that leads to increased airways resistance. Postnasal drip also has many associations with asthma as both can be presentations of the allergic phenotype. Therefore, GERD, postnasal drip, and asthma often coexist and treatment of all three conditions may be needed to resolve chronic cough. Asthma, however, can present as cough alone and should be considered as a diagnosis in those individuals who present with chronic cough.

Dyspnea and shortness of breath are common symptoms of asthma (Table 2.2 ). Many respiratory diseases, however, present with feelings of dyspnea; distinguishing asthma from other diseases, such as COPD, can be difficult when based on symptoms of dyspnea alone. To complicate matters, the perception of dyspnea in patients with asthma is variable and does not necessarily correlate with objective measurements of lung function. Most concerning are those patients whose perception of dyspnea is “blunted” despite having severe airways obstruction as measured by the forced expiratory volume in 1 s (FEV1). Briefly, the FEV1 is the volume of air exhaled in the 1st second of a forced expiration after a maximal inhalation. In other words, it is the amount of air exhaled after the patient is asked to take a deep breath in and blow out as hard as she can. The FEV1 is reported as a percent predicted, when compared to patients of the same height, age, sex, and race. A reduction in FEV1 is associated with increased airways resistance in patients with asthma. Several studies have shown that patients with substantial airways resistance have minimal symptoms. Furthermore, symptoms in general do not correlate with objective measures of lung function (Foo and Sly 1991 ; Hewson et al. 1996 ; Molema et al. 1989 ; Teeter and Bleecker 1998 ). Asking whether dyspnea is present or absent or even asking about the intensity of dyspnea may not be specific enough to assess the presence or severity of asthma. What may be more useful is understanding the language of dyspnea. Different respiratory diseases have distinct characteristics to their shortness of breath. This is not unlike cardiovascular disease and chest pain. Over the years, we have come to recognize different representations of ischemic chest pain and that not all patients present with the typical left-sided chest pain. We have now come to recognize jaw pain, arm numbness, indigestion, belching, and chest pressure as anginal equivalents. Similarly, dyspnea has many diverse characteristics and varying presentations.

Common symptoms of asthma

Researchers have compiled a group of phrases used to describe shortness of breath by patients with different lung and heart diseases that are listed in Table 2.3 (Simon et al. 1990 ). They found that patients experiencing an asthma attack chose phrases describing increased “work/effort” and “tightness” when asked to describe their dyspnea (Mahler et al. 1996 ). Further research has tried to assess the use of specific descriptors of dyspnea in assessing severity of an asthma attack. Moy et al. ( 1998 ) asked patients, in the midst of an asthma attack, to describe their feelings of shortness of breath (using Table 2.3 ) when they first presented to an emergency room and after treatment with bronchodilators. These patients were also asked to rate the severity of their dyspnea and were given breathing tests to objectively assess lung function. What was interesting was that these patients reported improvement in their feelings of shortness of breath after treatment with bronchodilators even if they had no improvement in their FEV1, an objective measure. Importantly, some aspects of their breathing discomfort improved more than others. For example, patients reported persistent feelings of increased “work” or “effort” of breathing, which better correlated with the severity of their diseases. In contrast, the sense of chest tightness improved after administration of bronchodilators. Moy et al. ( 1998 ) hypothesized that chest “tightness” may reflect bronchoconstriction, whereas “work” or “effort” may reflect ongoing inflammation and airways obstruction present during the later stages of an asthma attack. Therefore, medications that immediately dilate the airways by relaxing smooth muscles (such as bronchodilators) would provide relief from chest “tightness.” However, the “work” of breathing would persist because of obstruction due to ongoing airways inflammation. Unaware of these relationships between dyspnea and asthma, doctors may discharge patients from the emergency room or hospital before their lung function has improved (Salmeron et al. 2001 ). In a study of asthma management in French emergency rooms, 24% of patients with severe asthma were discharged 2 h after presentation when lung function was still poor (Salmeron et al. 2001 ). This may be because patients reported improvements in symptoms despite persistent airway resistance. Practitioners, therefore, should be cautious when interpreting the patient’s perception of dyspnea, and should attempt to distinguish between changes in chest tightness and the work or effort of breathing. Objective measures of lung function should be used routinely to manage patients in the midst of an acute exacerbation.

Descriptors of dyspnea

From Moy et al. ( 1998 )

Finally, the patterns of symptoms may help to diagnose asthma. For example, many asthmatics may have worse symptoms during certain seasons when allergies are increasingly prevalent. Others may have increased difficulty breathing at night or upon awakening in the early morning and may have improvements of their symptoms during the day. It is important to try and establish whether symptoms are persistent or episodic and whether certain triggers can be identified.

Diagnostic Tools

Medical history.

The medical history is one of the most important tools in diagnosing asthma. As mentioned earlier, common symptoms of asthma include episodic wheezing, cough, shortness of breath, chest tightness, increased work or effort of breathing, and difficulty inhaling. These symptoms, however, can occur with other respiratory illnesses, and taking a detailed history may help to support or refute the diagnosis of asthma. Going back to previous discussions on asthma pathogenesis, we outlined several hypotheses including the TH2 hypothesis, the hygiene hypothesis, the role of viral and bacterial illnesses, and the Dutch hypothesis. Understanding these hypotheses helps the clinician recognize factors that support the likelihood of asthma in an individual (Table 2.4 ). For example childhood onset of wheezing in association with other allergic symptoms would suggest TH2-mediated immune dysregulation and asthma. A family history of asthma and/or COPD could suggest a genetic propensity to develop respiratory disease in response to a particular insult as suggested by the Dutch hypothesis. Alternatively, a childhood history of RSV disease requiring hospitalization could suggest asthma as the etiology of his/her symptoms.

Asthma pathogenesis hypotheses and possible corresponding medical histories

Physical Exam

Often times the physical exam can be normal, especially if the patient is not having any symptoms of asthma. In those cases, one must rely on the medical history to help establish the diagnosis. If, however, a patient is experiencing symptoms at the time of the physical exam, there are some findings that increase the likelihood of asthma. For example, if airways obstruction is so significant that the patient cannot exhale all the air out before taking another breath, the lungs can become “hyperexpanded.” When hyperexpansion occurs, it is more difficult to breathe because the chest wall is at a mechanical disadvantage. Patients will begin to use “accessory muscles” to breathe. These muscles are not commonly utilized in quiet breathing, but if breathing becomes more labored they are recruited to assist in the movement of the chest wall. These accessory muscles include the neck muscles and abdominal muscles. Also, the activity of the intercostals muscles between the ribs can become more apparent during labored breathing. If breathing becomes more difficult, some patients will hunch over or assume the “tripod” position with their hands on their knees, leaning forward while sitting; this position transforms the pectoralis muscles, normally used to move the arms, into breathing muscles that elevate the chest wall.

After observing how the patient is breathing, auscultation of the chest can be informative as well. As discussed earlier, wheezing is a common sound of early airways obstruction. Usually a wheeze is heard on exhalation. With increasing airways resistance, however, inspiratory wheezes can be heard as well. The inspiratory to expiratory, or “I:E,” ratio is also reduced, meaning the expiratory phase is prolonged during airways obstruction. Usually, when listening to a patient’s chest, the clinician instructs the patient to breathe deeply, which results in an I:E ratio of 1:1. If airways obstruction is present, however, the I:E ratio can decrease to 1:2 because the lungs take longer to empty.

In cases of severe asthma attacks, a phenomenon called “pulsus paradoxus” can occur. The term “pulsus paradoxus” describes what happens to the pulse or systolic blood pressure during inspiration. Normally there is a slight weakening of the pulse during inhalation and a slight strengthening of the pulse during exhalation. This happens because of the small pressure swings in the chest that occur when we inhale and exhale and the effect that these slight changes of pressure have on the heart’s ability to pump blood. During a severe asthma attack, the work of breathing increases tremendously and the pressure swings in the chest become more pronounced. A person can generate −70 to −100 cm of H 2 O pressure (normal is between −2 and −5 cm of H 2 O pressure) which causes a severe strain on the heart’s ability to pump effectively. The pulse then becomes very weak during inspiration and returns during exhalation. This physical finding is called “pulsus paradoxus” and is a sign of severe airways obstruction and possible impending respiratory failure.

The rest of the physical exam can help to identify if the patient is prone to allergies. For example, examination of the nose may reveal mucosal swelling or nasal polyps to suggest allergic rhinitis. Similarly the eyes may be itchy, red, and teary. Skin exam may review rashes, such as hives or eczema, indicative of an allergic skin disorder. Taken together, if the physical exam is consistent with allergies in the context of shortness of breath and wheezing, the likelihood of asthma is increased.

Most imaging will be normal in patients with asthma. In some cases, one might see evidence of hyperinflation on a chest X-ray (CXR) with flattening of the diaphragm. The main purpose of imaging, however, is to assess the patient for other conditions that may mimic asthma such as chronic eosinophilic pneumonia, bronchiectasis, cryptogenic organizing pneumonia, and emphysema among other diseases. Additionally, a chest CT may be useful if the CXR is unrevealing but the suspicion of asthma is still suspect. Chest CT’s can more accurately show abnormalities of the airways, such as foreign bodies or tracheomalacia, which may be the cause of wheezing. It can also better image chronic bronchitis or bronchiectasis that may not be readily evident on a CXR. We recommend starting with a CXR in a patient newly diagnosed with asthma to exclude other possible causes of his/her symptoms.

Pulmonary Function Tests

Pulmonary function tests can be very helpful in diagnosing asthma. As mentioned earlier, measurement of FEV1 is important in diagnosing airflow obstruction. FEV1 is the amount of air exhaled during the 1st second of a forced exhalation after maximal inhalation. The forced vital capacity (FVC) is the amount of air exhaled in total after the patient blows out for as long as possible (at least 6 s); the air remaining in the lungs after such a maneuver is the residual volume (RV). If the FEV1/FVC ratio is less than what would be predicted for that person, then airflow obstruction is present. However, diseases such as chronic bronchitis, emphysema, or cystic fibrosis, all present with airflow obstruction. What increases the likelihood of asthma is the reversibility of the airflow obstruction. Often times in the lab, when we suspect that a person has asthma, we will assess the FEV1 and FVC before and after a bronchodilator. If the FEV1 increases by as least 12% and 200 cc, the patient has a significant response to bronchodilators suggestive of asthma. Wide variations in FEV1 over time with repeated pulmonary function testing are also suggestive of asthma. However, because these tests are very effort dependent, fluctuations in FEV1 can be due to patient effort rather than true reversible airways disease. In moderate to severe asthma, the patient may not be able to exhale fully during the vital capacity maneuver. The result is a diminished FVC and an elevated RV.

There are many instances when patients will not be experiencing airflow obstruction during pulmonary function testing, making it harder to diagnose asthma. Another strategy is to ask the patient to measure his PEF at home at various times during the day. This can be accomplished by asking the patient to use an inexpensive peak flow meter. Similar to the FEV1 measurement, the PEF assesses the rate at which air exits the lung during a forced expiration after maximal inspiration. In asthma, PEF is usually lowest in the morning and highest between noon and 2 p.m. (Quackenboss et al. 1991 ). The patient makes PEF measurements several times a day and a 20% difference in values between the highest and lowest flow measurements is suggestive of asthma.

If, after obtaining the history, physical exam, CXR, and pulmonary function tests, the diagnosis of asthma is still in doubt, a bronchoprovocation test to induce airways obstruction may help to establish or exclude the diagnosis. Commonly, a bronchoprovocation test is useful when conventional therapies for asthma do not resolve the patient’s symptoms. The physician must decide whether to intensify the medical regimen or question the diagnosis of asthma. A MCT can help confirm or exclude a diagnosis of asthma and guide further therapy (Fig. 2.3 ).

Algorithm for asthma diagnosis

The hallmark of asthma is bronchial hyperresponsiveness, meaning that the airways constrict robustly in response to an irritant or other stimulus. Methacholine is a medication that causes constriction of the smooth muscles around the airways. When given in high enough doses, a person with normal airways can have bronchoconstriction with methacholine. In asthmatics, however, the airways will constrict with very small doses that usually do not affect the normal airway. The MCT is administered in a monitored setting. The subject inhales a solution of methacholine in increasing doses. After each inhalation, FEV1 and FVC are measured. If there is a decrease of 20% in the FEV1 after an inhalation of a certain dose of methacholine, the test is stopped. This is called the PC20, the provocation concentration that is required to decrease the FEV1 by 20%. As outlined in the Table 2.5 , the degree of bronchial hyperresponsiveness depends on how much methacholine is required to cause significant bronchoconstriction. The MCT is a useful test for diagnosing asthma but the results must be interpreted in the context of all the information known about the patient. It is not 100% diagnostic.

Degree of bronchial hyperreponsiveness after administration of methacholine

From ATS AJRCCM 2000 (Crapo et al. 2000 )

Although the MCT is not a foolproof test, it is helpful in trying to obtain the correct diagnosis in a patient with asthma-like symptoms. In a study of patients evaluated for dyspnea and cough who did not improve with asthma treatment, 82.5% had negative MCT (Chevalier and Schwartzstein 2001 ). As a result of these negative tests, bronchodilators were discontinued and other causes for dyspnea and cough were pursued and then treated. Other studies have shown that even a previous history of asthma did not reliably predict a positive MCT (Pratter et al. 1989 ). The MCT, therefore, is a powerful tool to help establish the diagnosis of asthma in some cases and exclude it in others, thereby allowing the patient to receive the treatment she needs.

Mimickers of Asthma

All that wheezes is not always asthma. Often times, in difficult cases, other diagnoses should be explored if the diagnosis of asthma is in question. These are usually cases in which the patient does not respond to treatment or has a physical exam or history that seems inconsistent with asthma. The mimickers of asthma can be categorized into diseases affecting the large airways, small airways, and lung parenchyma. Non-pulmonary causes should also be considered.

One of the most difficult diagnoses to make is vocal cord dysfunction (VCD). VCD can present like asthma and patients usually have a history of asthma that has not been responsive to steroids or bronchodilators. Because they continue to wheeze despite therapy, these patients can be exposed to large doses of steroids and bronchodilators putting them at risk for complications of these medications. Although the etiology of VCD is not fully elucidated, it is more common in young adults with psychiatric disorders. It occurs when the vocal cords adduct (come together in the midline) during inhalation and exhalation creating airflow limitation at the level of the vocal cords. The lungs and airways themselves, however, are normal. The patient adducts the vocal cords subconsciously and can often appear to be in respiratory distress. VCD presents with similar symptoms and signs as asthma, such as shortness of breath and wheezing. In extreme cases, however, patients with VCD can hypoventilate and be intubated for respiratory failure. Unlike asthma, however, wheezes cease after intubation because the endotracheal tube bypasses the vocal cords, the site of obstruction. After intubation, the patient with VCD is easily ventilated and can be removed from mechanical support within 24 h.

Definitive diagnosis of this disorder can be difficult and usually requires direct visualization of the vocal cords during symptomatic episodes. Physical exam during an episode usually reveals a monophonic wheeze heard loudest over the throat. Patients may have trouble vocalizing while wheezing and symptoms can come on suddenly without warning. Treatment requires intense speech therapy during which these patients learn techniques for relaxed throat breathing. With treatment, patients with VCD can come off steroids and bronchodilator therapy and live a better quality of life. In extreme cases, a tracheostomy is performed to bypass the site of recurrent obstruction.

Other problems of the large airways that can cause wheezing included foreign bodies in the large airways. Aspiration of nuts or other food products can cause foreign bodies to get trapped in a large airway. In severe cases, these foreign bodies can act as a ball-valve causing hyperinflation and eventual respiratory distress. Immediate removal of the foreign body by a trained bronchoscopist is required. Besides aspirated objects, congenital abnormalities, such as vascular rings or laryngeal webs, can cause obstruction of the trachea and lead to wheezing and shortness of breath. Other masses, such as tumors, can cause obstruction of the airways as well and with similar presenting symptoms. Lung cancer and carcinoid tumors may cause focal airway obstruction. In patients who have had prior intubations, tracheal stenosis as a late complication of endotracheal intubation can also present like asthma. A bronchoscopy to inspect the airway is usually required to make this diagnosis. Even if the airway is normal, structures outside of the airway can be abnormal and can cause compression resulting in obstruction. Lymph nodes, vascular structures, or tumor can impinge upon the large airways in this manner. Often times, a chest CT is helpful in making this diagnosis.

Sometimes the airways can be affected by other disease processes such as bronchiectasis. Bronchiectasis is a common disorder that can present with signs and symptoms similar to asthma. Patients with bronchiectasis have distorted and abnormal airways usually due to an infectious process. People can develop bronchiectasis as a sequelae of a severe necrotizing lung infection or toxic gas exposure. In necrotizing pneumonia, the abnormal airways usually are confined to the region of the lung where the original infection took place, whereas toxic gas exposure can cause more diffuse bronchiectasis. Because the airways are abnormal, it becomes more difficult to clear infections from bronchiectatic lung and recurrent infections occur. Some patients develop bronchiectasis after aspirating a foreign object that gets lodged in the airway. The object makes it difficult to clear pus, creating recurrent persistent infections and progressive damage to the airway. Other patients may develop bronchiectasis as a result of an underlying condition that makes the patient prone to lung infections and impairs the ability of the body to clear infections despite appropriate antibiotics. Such conditions include cystic fibrosis (a genetic disorder causing thick mucous plugs that are difficult clear) and immunodeficiency states. Regardless of the underlying cause for bronchiectasis, the presentation is similar with daily cough productive of purulent sputum, recurrent pulmonary infections, shortness of breath, and wheezing. The wheezing associated with bronchiectasis may be due to airflow obstruction associated with mucous plugging or distorted airways. Unlike asthma, the airflow obstruction is not completely reversible. Asthma, however, can also exist concomitantly with bronchiectasis. If a patient with wheezing has recurrent pulmonary infections or daily cough productive of purulent sputum, the diagnosis of bronchiectasis should be considered. Chest imaging can determine if the airways are distorted or abnormal to confirm the diagnosis of bronchiectasis.

Other airway diseases can also mimic asthma. In children, congenital abnormalities such bronchopulmonary dysplasia should be considered. In adults, diseases such as sarcoidosis can cause wheezing, cough, and dyspnea as well. Sarcoidosis is a disease of unclear etiology in which non-caseating granulomas affect the lymph nodes and airways. Airway or lymph node biopsy is often required to make the diagnosis. Diseases such as COPD are also common in adults and can mimic asthma as well. Occasionally, asthma and COPD can coexist.

Diseases that affect the lung parenchyma can cause wheezing, cough, and shortness of breath. Chronic eosinophilic pneumonia, in which eosinophils infiltrate the peripheral lung parenchyma, can present with wheezing and usually requires high doses of steroids to treat. Hypersensitivity pneumonitis is also a disease of the lung parenchyma, usually affecting the upper lobes and precipitated by exposure to some inhaled substance such as mold, flour, bird allergens, etc. Hypersensitivity pneumonitis can present acutely with fevers, cough, and dyspnea or less acutely with cough, wheezing, and shortness of breath. Other diseases that affect the lungs, such as pulmonary emboli or pneumonia, can also mimic asthma. Imaging, careful history, and physical exam may help to distinguish these conditions from asthma.

Processes that affect the pulmonary vasculature can also present as asthma does. As noted above pulmonary embolism can present with shortness of breath and wheezing. Although wheezing is not a common symptom of pulmonary embolism, it has been reported in the medical literature (Calvo-Romero et al. 2003 ). Although the etiology of wheezing in pulmonary embolism is not clear, possible mechanisms include an inflammatory reaction resulting from the embolism or the release of chemicals such as bradykinin that may lead to bronchoconstriction and wheezing. Congestive heart failure can also cause dyspnea, cough, and wheezing (often termed cardiac asthma) due to pulmonary edema. When the heart fails to pump adequately, fluid builds up in the pulmonary lymphatics and pulmonary venous capillaries, which then causes edema of the lungs and can promote wheezing.

Other conditions that may mimic asthma include reactions to medications such as angiotensin converting enzyme I inhibitors (ACE-I), which can cause chronic cough. GERD can also cause both cough and bronchoconstriction as mentioned earlier. Aspiration can cause wheezing and cough due to inflammation of the airways. In cases of GERD, the patient may be unaware of these episodes. In severe cases, if routine treatment of GERD (including proton pump inhibitors and behavioral modification) does not alleviate the problem, procedures to tighten the lower esophageal sphincter are needed to prevent reflux.

A careful history, physical exam, and clinical acumen are required to identify when a diagnosis of asthma just doesn’t seem right. Clues, such as poor response to asthma therapy, persistent instead of episodic symptoms, or constitutional symptoms (weight loss, fever, nausea/vomiting), can be useful in stimulating a search for non-asthma diagnoses. Chest imaging can be helpful in excluding diseases of the lung parenchymal, and bronchoscopic imaging may further help diagnose large airways obstruction.

We have briefly reviewed general theories of asthma pathogenesis including the TH2 hypothesis, the hygiene hypothesis, the Dutch hypothesis, and the role of infectious diseases in asthma. These theories demonstrate that asthma is a heterogeneous disease with multiple causative mechanisms in susceptible individuals. We reviewed the physiology of asthma and its relationship to symptoms such as dyspnea. We outlined a diagnostic approach to asthma based on symptoms, history and physical exam. In cases in which the asthma diagnosis is still in question, a MCT may help to support or exclude the diagnosis. Finally, an awareness of conditions that mimic asthma is important when confronted with a patient who may have atypical features or who fails to respond to therapy.

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Spring Allergy Season Is Getting Worse. Here’s What to Know.

Experts explain how to tell if you have allergies, and how to find relief if you do.

By Nina Agrawal

Spring is here — and if you’re among the estimated one in four adults in the United States who suffers from seasonal allergies, your sneezing and scratching may have already started.

With climate change affecting temperatures and plant growth, you may need to be on the lookout earlier than ever before. It can be hard to distinguish allergy symptoms from those of a cold, but experts point to a few telltale signs.

Is allergy season getting worse?

Spring allergy seasons are beginning about 20 days earlier than they had, according to an analysis of pollen count data from 60 stations across North America from 1990 to 2018.

That shift can have significant health consequences, said William Anderegg, who is an author of the study and an associate professor of biology at the University of Utah. Other research has shown that very early onset of spring is associated with higher prevalence of allergic rhinitis, also known as hay fever. When people end up sick or in the hospital from uncontrolled allergy symptoms, he said, “it’s because they didn’t expect it, and didn’t have medications in hand.”

The researchers also found that pollen concentrations have risen about 20 percent nationwide since 1990, with Texas and the Midwest having the greatest increases. Warmer temperatures, higher concentrations of carbon dioxide and increased precipitation can all contribute to plants’ growing bigger and producing more pollen over longer periods of time, Dr. Anderegg said.

Dr. Gailen Marshall, chair of the allergy and immunology department at the University of Mississippi Medical Center, said that when he began practicing nearly 40 years ago, allergy seasons were confined to about eight weeks each. Tree pollen hit in the spring, grass pollen increased in spring and summer and ragweed pollen picked up in late summer and early fall.

Back then, people “could at least get some relief” between those cycles, said Dr. Marshall, who is also president of the American College of Allergy, Asthma and Immunology, a professional organization. “Now, these seasons end up becoming one long season.”

How can you tell whether it’s allergies or a cold?

Many people with nasal congestion or a runny nose may assume that they have a cold. Though allergy and cold symptoms can be similar, allergies often make the eyes, nose, throat, mouth or ears itchy, said Dr. Rita Kachru, chief of clinical allergy and immunology at UCLA Health. With allergies, the immune system mistakes a trigger, like pollen, for a harmful substance. When repeatedly exposed to that trigger, Dr. Kachru said, immune cells release chemicals, including histamine, that cause itchiness and inflammation.

Patients also often experience congestion and postnasal drip, or mucus dripping down the back of the throat. Some people may develop coughing, wheezing and shortness of breath.

With a viral infection, by contrast, you might have muscle fatigue, joint aches or a fever.

If your symptoms flare up every year around a certain season and last more than a week or two, then there is a good chance they’re being caused by allergies. A personal or family history of allergies, eczema or asthma can also be an important clue, doctors said.

What if I’ve never had allergies before?

Most people first develop symptoms in childhood or young adulthood. But several experts said it’s not uncommon for someone to have seasonal allergies for the first time as an adult.

Moving to a different part of the country and being exposed to different allergens may provoke a response, Dr. Kachru said.

New allergy symptoms in adulthood could also be “an inevitable consequence of really soaring pollen counts,” said Dr. Neeta Ogden, a New Jersey-based allergist.

The increase in winds associated with climate change could be distributing pollen farther, potentially exposing people to new varieties of it, said Dr. Mary Johnson, a research scientist at Harvard.

Research has also shown that hormones, including estrogen, progesterone and testosterone, can affect how allergic diseases develop.

Boys often have food allergies or eczema as babies and seasonal allergies or asthma in childhood but then have those conditions disappear when they hit puberty, Dr. Kachru said. But symptoms can return when they reach their 30s and 40s.

For some women, major hormonal shifts, including those that happen during puberty, pregnancy and menopause and while on birth control, can affect the onset and severity of allergy symptoms, Dr. Kachru said.

How do I manage the symptoms?

The first step is to reduce exposure. Keep your windows shut to prevent pollen from blowing into your home.

“The key is to prevent the outdoor allergens from becoming indoor allergens,” said Dr. William Reisacher, a professor of otolaryngology who treats allergies at Weill Cornell Medicine and New York-Presbyterian.

To help do so, take off the clothes you’ve worn outside when you get home and store them outside your bedroom. Then take a shower to rinse the pollen off your skin. Doctors recommend a saline nasal rinse to flush the pollen out of your nose. (If you make your own, be sure to use boiled, sterile or distilled water. )

Over-the-counter medications fall into two main categories: antihistamines and steroids. Both act on your immune system’s inflammatory response. Antihistamines are available as nasal sprays, eye drops and oral pills, including loratadine (Claritin), cetirizine (Zyrtec), levocetirizine (Xyzal) and fexofenadine (Allegra).

Steroids come as nasal sprays, including fluticasone (Flonase), budesonide (Benacort), triamcinolone (Nasacort) and mometasone (Nasonex).

If you have symptoms for the first time and aren’t sure how bad they’ll be or how long they’ll last, Dr. Kachru said, try an antihistamine to see if it helps.

If the symptoms persist, or you know that you get hit hard with allergy symptoms every spring, doctors recommend nasal sprays. Unlike antihistamines, which should be used only as needed, these steroids work best if you start using them a week or two before symptoms begin.

Doctors caution against using products with pseudoephedrine, such as Sudafed, for more than a day or two because they can increase heart rate and blood pressure. In 2020, a task force of physicians that issues guidelines for treating allergies recommended against using Benadryl to treat allergic rhinitis; doctors said it can have sedative effects and cause confusion.

If avoiding environmental triggers and taking medication don’t work for you, allergy shots or tablets that build your tolerance to allergens might help.

“It’s the only option available that actually makes the body less allergic,” Dr. Reisacher said.

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