Carisa D. Brewster

While there may not always be a biological cause for dysfunctional breathing (DB), it is a common comorbidity in 

. A recent study has found that DB can also be associated with sinus issues, some psychological disorders, and unemployment.

DB is a collection of breathing disorders that demonstrate a change in breathing pattern that results in breathlessness, according to the American Academy of Allergy, Asthma and Immunology (AAAAI). There are multiple breathing patterns that may present themselves, including hyperventilation, deep sighing, thoracic-dominant breathing, and mouth breathing. However, the condition is still highly enigmatic, and diagnosis can be difficult.

Investigators, led by Eve Denton, MBBS, MPH, of Alfred Hospital in Melbourne, Australia, have conducted past research detailing the high occurrence of DB among those with severe asthma. For this current study, their goal was to identify other risk factors in this population that may contribute to the development of DB.

Participants included 157 adult patients under care in Alfred’s asthma program from June 2014 through December 2017. Symptoms included severe or frequent asthma exacerbations despite treatment, inadequate control of asthma symptoms, unclear diagnosis, severe airflow obstruction, or asthma management issues.

Patients completed asthma and comorbidity questionnaires at baseline, lung function tests, and skin prick tests. Asthma control was evaluated using the six-item Asthma Control Questionnaire (ACQ 6) and quality of life using Asthma Quality of Life Questionnaire (AQOL).

DB was diagnosed with a Nijemgen Questionnaire score greater than 23 and with matching clinical symptoms that include excessive dyspnea. Additional comorbidities that were assessed included psychiatric history (using the Hospital Anxiety and Depression Scale [HADS]), atopy, allergic rhinitis, chronic rhinosinusitis, sleep apnea, gastroesophageal reflux, and vocal cord dysfunction (VCD).

Almost half (47%) of the participants experienced DB, with female patients more likely to be diagnosed (24 vs. 20; 

= .04). Those with DB also had a higher chance of being unemployed (44% vs. 61%; 

= .04), have higher exacerbations (3 vs. 2.5; 

= .037), worse asthma control (ACQ 6 2.8 vs. 2.1; 

= .001), and worse quality of life (AQOL 3.8 vs. 4.6; 

Overall, psychiatric comorbidity was significant for depression (29%) and anxiety (25%). Patients with DB had more anxiety (41% vs. 11%; 

= .001). HADS scores were also higher for anxiety (10 vs. 5.3; 

< .001). Sinus symptoms, anxiety, and depression were also independent risk factors for DB.

“Dysfunctional breathing is a common but under-recognized cause of excessive breathlessness in [the difficult asthma] population and it is important to identify due to the potential for treatment,” investigators wrote. “Breathing retraining in those with mild to moderate asthma improves quality of life and recent data from our group suggests similar benefits in more severe asthma.”

Also of note: there was no association found between lung function impairment or inflammatory biomarker levels (IgE, atopic status, and eosinophil count) and DB diagnosis. Investigators noted this emphasizes the need to explore DB in patients with severe asthma regardless of poor lung function or inflammatory phenotype.

Factors Associated with Dysfunctional Breathing in Patients with Difficult to Treat Asthma

The Journal of Allergy and Clinical Immunology.

Articles

Dysfunctional breathing is a common comorbidity in patients with severe asthma, and is associated with increased patient anxiety and depression.

Asthma Patients Require Increased Detection of Dysfunctional Breathing

 exacerbations are intermittent, it can be a challenge to obtain enough subjects to properly assess the clinical effect of a treatment. A new study reveals that a novel endpoint for asthma, CompEx, could help determine the efficacy of an asthma therapy using smaller trial sizes and time periods.

CompEx, developed by AstraZeneca (AZ) in collaboration with researchers from the Universities of Colorado and Lund, combines deteriorations and frequency of asthma exacerbations that are recorded twice daily by patients. An algorithm is developed based off of patient deterioration below threshold limits and gradual deterioration over a five-day time frame.

The study, led by Göran Eriksson, Hendrick Nolte, and Christian Ljørring, Department of Respiratory Medicine at Lund University Hospital, Sweden, applied CompEx post-hoc to data from MITRA, a large phase 3 house dust mite (HDM) sublingual immunotherapy (SLIT) tablet allergic asthma trial.

During the trial, MITRA used an adapted version of the definition of moderate to severe asthma exacerbations established by the American Thoracic Society and the European Respiratory Society (ATS/ERS). Investigators wanted to compare results from CompEx to the results that implemented the ATS/ERS version (which was also modified to increase sensitivity in asthma trials).

In the MITRA trial, 834 participants were randomized to once-daily treatment of placebo or HDM SLIT tablet (6 SQ-HDM or 12 SQ-HDM). To qualify for the trial, candidates had to have a history of house dust mite allergic asthma for 1 year or more, associated rhinitis not controlled by inhaled corticosteroids (ICS), and positive tests for house dust mite sensitivity.

Participants kept a diary of data on peak expiratory flow, reliever use, and asthma symptoms, all documented each morning and evening, including nighttime awakenings, during the 6-month efficacy period.

Severe asthma exacerbations were defined as use of systemic corticosteroids or a hospital/emergency room visit due to asthma, as labeled by ATS/ERS. For CompEx, an exacerbation transpired when an ATS/ERS defined exacerbation occurred or when a diary event occurred.

At the three-month assessment, CompEx showed a 25% exacerbation rate with 12 SQ-HDM and placebo, compared to 19% with moderate/severe events. At the six-month assessment, CompEx still maintained a higher rate at 34%, versus 28% for moderate/severe events. Time to first event for 12 SQ-HDM and placebo was also evaluated, resulting in lower 

 values for CompEx when compared to moderate/severe events.

Overall, there was a 30% reduction in the number of patients needed per group for CompEx versus using the moderate/severe definition.

“The increased event rate after 3 months of ICS reduction combined with the lower p-values imply that using CompEx would allow conduct of an allergic asthma trial with a shorter duration or fewer subjects, while still maintaining statistical power,” investigators wrote.

Comparison of the novel CompEx asthma exacerbation endpoint to the ATS/ERS adapted moderate/severe asthma exacerbation definition used in the MITRA trial

CompEx combines deteriorations and frequency of asthma exacerbations that are recorded twice daily by patients. An algorithm is developed based off of patient deterioration below threshold limits.

Novel CompEx Endpoint Could Improve Asthma Therapy Assessments

While lung function decline is a normal feature of aging, having 

 changes the game entirely. Severe exacerbations predict decline, but a new study shows that monitoring blood eosinophil counts over time shows promise as a simpler method.

Investigators—led by PhD student Sophie Graff, Dr. Sophie Demarche, and Monique Henket from the Department of Respiratory Medicine at University of Liege in Belgium&mdash; said that while asthma patients have lower lung function than asthma-free populations, not all patients have declining lung function. For some, the disease stabilizes, and others can even outgrow asthma.

But asthma patients remain at risk for airway remodeling, which results in airflow defects and low forced expiratory volume over 1 second (FEV

Other risk factors for lung function decline include low baseline FEV

, airway hyper-responsiveness, being male, cigarette smoking, late asthma onset, and duration of disease. Study investigators also noted that past research has shown associations between eosinophilia (high blood eosinophil levels) and lung function decline.

“The purpose of this study was to evaluate potential risk factors for accelerated lung function decline in a secondary care asthma population, including evolution of blood sputum eosinophils and neutrophils over time,” investigators wrote.

Subjects included adult patients with asthma from the University Asthma Clinic of Liege in Belgium. To be eligible, participants had to have at least 2 visits void of exacerbations with post-bronchodilation (BD) FEV

measurements and minimum of 1 year between them. After study criteria was met, 229 patients seen between February 2004 and January 2017 qualified.

Quality of life, fractional exhaled nitric oxide (FeNO), spirometry, sputum induction and blood sampling (eosinophil and neutrophil counts), FEV

decline, and treatment dosages (inhaled corticosteroids [ICS], antileukotrienes, long-acting muscarinic antagonists [LAMA], long-acting beta-2 agonists [LABA], anti-IgE, anti-IL5, and oral corticosteroids [OCS]) were measured.

Declines in lung function, both post-BD FEV

, were linked to an increase of blood eosinophil levels over time (0.42 [95% CI: 0.21- 0.63; 

< .0001]) and longer gaps between follow-ups (12.6 months; 95% CI: 10.4-14.7; 

Close to half (42%) of patients had severe asthma and uncontrolled even with high doses of ICS or LABA. Of those with severe asthma, 52% had the eosinophilic inflammatory phenotype.

“We are the first to show that a significant increase in systemic eosinophilic inflammation, even in patients with normal baseline value, can predict FEV 1 decline,” investigators noted. “This has clinical implications, as blood collection is easily measured, more widely available with a higher success rate, and less time consuming than sputum collection.”

“Increase in blood eosinophils during follow-up is associated with lung function decline in adult asthma,”

Close to half of observed patients had severe asthma and uncontrolled even with high doses of ICS or LABA. Among them, more than half had the eosinophilic inflammatory phenotype.

Blood Eosinophil Increase Can Predict Asthma Lung Function Decline

While nasal polyposis does not cause asthma, it can cause chronic rhinosinusitis, which in turn can exacerbate 

. Diagnosis usually involves endoscopy or imaging, but a new study found that the less invasive fractal exhaled nitric oxide (FeNO) test might improve nasal polyposis detection in those with severe asthma.

According to the American Academy of Allergy, Asthma, and Immunology (AAAAI), 26% to 56% of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) have asthma. The combination can cause breathing and other nasal symptoms to become worse.

Along with asthma exacerbations, symptoms might include nasal drainage and congestion, a decrease in or loss of sense of smell, and facial pain.

It is not known why nasal polyposis develops, but biopsies of polyp tissue have shown elevated eosinophil levels. Certain cells associated with inflammation produce nitric oxide, which makes the FeNO test a reliable indicator of asthma.

The purpose of this study, explained by investigators—led by Mauro Maniscalco, MD, PhD&mdash;is to explore the relationship between FeNO levels and nasal polyposis.

Subjects included 93 patients with asthma getting care at 4 specialty clinics in Italy between 2015-2018. All had severe asthma with treatment plans that included daily doses of inhaled corticosteroids (ICS). To construct a baseline, patients completed a questionnaire on medical history and then given atopy assessments, and spirometry. On a second visit, blood eosinophil and FeNo levels were calculated.

Results showed that high eosinophil count (>420 cells/mm

) and higher FeNo levels (39 ppb or greater) were associated with nasal polyposis. In addition, out of the 28 patients that had nasal polyposis, 3 had both low eosinophil counts and FeNO, but 25 had either high eosinophil levels or FeNO. Adding FeNO seemed to improve classifying patients who have nasal polyposis, but have low blood eosinophil levels.

“The results from our study suggest investigating nasal polyposis comorbidity in all severe asthmatic patients with elevated FeNO levels, including the subgroups with normal or low blood eosinophil count,” investigators wrote.

Limitations included the patient population size, 11 subjects being current smokers, and ICS treatment, as both smoking and ICS can impact FeNO levels.

 while at the AAAAI 2018 Annual Meeting last year, Marc Massanari, PharmD, explained that FeNO monitoring plays a critical role in promptly and effectively treating patients with asthma.

“There really is no other biomarker test on the market today that allows a clinician at the bedside to know how inflammation is in a patient’s lung,” Massanari said. “So it’s an important test, and I think it has a very large impact on the clinician to then assess the patient and improve their level of asthma control.”

“Association between exhaled nitric oxide and nasal polyposis in severe asthma,”

Approximately one-half of patients with chronic rhinosinusitis with nasal polyposis have asthma. The less-invasive FeNO test may help detect comorbid patients.