Cough-Variant Asthma

Asthma is one of the most common causes of chronic cough (24–29%) in adult nonsmokers. In asthma, cough is usually associated with dyspnea and wheezing. However, cough may present in isolation as a precursor of typical asthmatic symptoms, or may be the sole symptom of asthma. This condition is termed as cough-variant asthma (CVA).¹ Multiple studies have revealed that 30% to 60% of adult subjects who are nonsmokers with chronic cough have cough-variant asthma.² The other common causes of chronic cough are shown in Figure 1.³

Epidemiology of CVA

• Chronic cough is the fifth most common complaint encountered by the primary care physicians in the world.³
• In the USA, chronic cough accounts for up to 38% of pulmonologists outpatient practice.³
• In China, CVA accounts for 14% to 51% of chronic cough.⁴

Epidemiology of CVA: Indian scenario

• A common cause of isolated cough in India is cough-variant asthma. It accounts for around 30% of cough referrals to cough clinics.⁵
• An epidemiological study on bronchial asthma conducted in South India reported the prevalence of cough-variant-asthma as
• 50.83%, nocturnal asthma as 17.5%, allergic asthma as 20.83%, and occupational asthma as 10.83%.⁶

Asthma syndromes comprise classic asthma, cough-variant asthma, eosinophilic bronchitis, and atopic cough.³

Definition

Cough-variant asthma is defined as a type of asthma characterised only by chronic dry cough lasting for 8 weeks or longer, without wheezing, dyspnea, or any apparent cause.^{7, 8}

The features of CVA are as follows: ^{7, 8}

• Airway hyper-responsiveness/bronchial hyperactivity
• Normal chest examination
• Normal chest radiography
• Normal blood count, except eosinophilia
• Normal spirometry
• Response to bronchodilator and/or steroid inhalation treatment

Cough-variant Asthma Phenotype²

• Cough-variant asthma denotes a different phenotype from those with classic allergic asthma or with eosinophilic bronchitis, due to the absence of dyspnea and wheezing, and presence of mast cells located in airway smooth muscle, which has been shown to be linked with airway hyper-responsiveness.
• Presence of airway hyper-responsiveness to nonspecific stimuli, eosinophilic airway inflammation, and a favourable response to asthma treatment are key to the diagnosis of this phenotype.

Etiopathogenesis

Etiology

Unlike classic or typical asthma, etiology of CVA is not known. Seasonal variation of symptoms is very common in CVA, which may indicate atopy.⁹ Chronic cough may also follow an upper respiratory infection. Aggravating factors for CVA are shown in Box 1.⁷

Box 1: Aggravating factors of CVA⁷

• Cold, and warm air
• Passive smoking
•  Conversation
• Exercise
• Alcohol
• Mental stress

Pathophysiology

• Cough-variant asthma has a number of pathophysiological features of classic asthma, such as atopy, airway hyper-responsiveness, eosinophilic airway inflammation, and various attributes of airway remodeling.⁹
• Imbalance between the production of bronchoconstrictor leukotriene C4 and bronchoprotective prostaglandin E4 lipid mediators may cause development of CVA.⁸
• In CVA, eosinophils increase in the sputum bronchoalveolar lavage (BAL) fluid and bronchial mucosal tissue; the degree of this increase relates with the severity of disease.⁹

• Concomitant increase of neutrophils and eosinophils in the airway mucosa of CVA patients may indicate more severe disease.⁹
• Mast cells, an important source of tussive and fibrogenic mediators, were found to have increased in the airway mucosa of nonasthmatic chronic cough patients, but not in CVA patients.⁹
• Structural changes such as subepithelial thickening, goblet cell hyperplasia, and vascular proliferation have been verified in mucosal biopsies of CVA, similar to asthma.⁹
• These changes may indicate early anti-inflammatory treatment in patients with CVA.⁹
• A computed tomography (CT) study has shown airway wall thickening, a feature of chronic asthma, in patients with CVA, which may reflect the net effect of airway remodeling features.⁹
• A study on the pattern of inflammatory sputum markers in patients with asthma and CVA found no significant differences in the levels of eosinophilic cationic protein (ECP), interleukin (IL)-8, tumour necrosis factor alpha (TNF-α), and the levels of exhaled nitric oxide (eNO).¹⁰
• Histamine was correlated with IL-5 in CVA, whereas it was associated with sputum eosinophilia in classic asthma.⁵
• Pathophysiological differences among CVA, atopic cough, and eosinophilic bronchitis are shown in Table 1.³

About 25% of patients with CVA appear to develop clinically full- blown bronchial asthma.⁸

Clinical Features

CVA can be considered as a subtype of bronchial asthma and usually presents with:

• Chronic nonproductive cough lasting 8 weeks or more with little or no dyspnea.^9,11
• More severe cough at bedtime, during the night, and in the early morning.⁷

Differential Diagnosis

• Response to steroid therapy in CVA does not exclude the diagnosis of eosinophilic bronchitis and atopic cough, which are also accompanied by chronic cough.1 Therefore, CVA needs to be differentiated from these two conditions. Differential diagnosis for cough-variant asthma is addressed in Table 1.³

Diagnosis

The diagnosis of CVA presents a challenge as physical examination and pulmonary function tests may be entirely normal.¹

• Methacholine challenge test: Methacholine-induced bronchoconstriction produces opposite effects in CVA and classic bronchial asthma (Figure 2).¹²
• Improvement with bronchodilators: Diagnosis of CVA is confirmed only after the resolution of cough with specific anti-asthmatic therapy.¹ Japanese Respiratory Society cough guideline considers responsiveness to bronchodilators as the key diagnostic feature of CVA.⁹
• Pulmonary function test and bronchial hyper -responsiveness: Chinese National Guidelines on diagnosis and management of cough, recommends pulmonary function test and bronchial hyper-responsiveness (BHR) as the first-line test for the diagnosis of CVA; however, BHR is a time-consuming and labor dependent test.⁴

• Measurement of fractional exhaled nitric oxide (FeNO): It is a noninvasive, reproducible, and sensitive method for differentiating CVA from chronic cough.4 Exhaled nitric oxide levels may be elevated and beneficial in the diagnosis of CVA.⁹

Diagnostic Criteria for CVA

The diagnostic criteria for CVA are shown in Box 2.³

Box 2: Diagnosis of cough-variant asthma proposed by Japanese Cough Research Society³

• Isolated chronic nonproductive cough lasting more than 8 weeks
• Lack of a history of wheeze or dyspnea
• No adventitious lung sounds on physical examination
• Absence of postnasal drip to account for the cough
• Forced expiratory volume in 1 sec (FEV ), forced vital capacity (FVC), and FEV /FVC ratio within normal limits  1
• Presence of bronchial hyper-responsiveness (provocation concentration, PC 20 <10 mg/mL)
• Cough reflex sensitivity within normal limits (C5 >3.9 mmol/L)
• No abnormal findings indicative of cough etiology on chest radiograph
• Relief of cough with bronchodilator therapy

Therapeutic Approaches for Cough-variant Asthma

• Therapy for CVA follows the same stepwise approach as typical asthma.
• The American College of Chest Physicians clinical practice guidelines recommend inhaled bronchodilators and inhaled corticosteroids as the first regimen for CVA patients.¹
• Presence of airway eosinophilia indicates need for more aggressive anti-inflammatory therapy.¹
• Evaluation of the airways is necessary for the addition of leukotriene receptor antagonists, and if this regimen fails, a short course (1–2 weeks) of oral corticosteroids, followed again by inhaled corticosteroids, is recommended.¹³
• Treatment for the aggravating factors such as rhinosinusal conditions, gastroesophageal reflux, or psychotic conditions is recommended before escalation of therapy.¹³
• Partial improvement is often attained after 1 week of inhaled bronchodilator therapy, but complete resolution of cough may require up to 8 weeks of treatment with inhaled corticosteroids.¹
• A brief description of therapeutic agents for CVA is shown in Figure 3.¹³
• The recommendations for the management of CVA are presented in Figure 4.

Psychological factors, such as ’frustration’, ‘fright into illness’, and ‘distorted lifestyle,’ were more prominent in patients with CVA than in patients with classic asthma.¹³

Other Therapies for CVA¹³

• Antihistamines such as azelastine have been shown to be effective in CVA therapy.
• Phosphodiesterase 3 and 4 inhibitors represent a better therapeutic alternative to classically used theophylline, but clinical data are lacking.

Effect on Quality of Life

Depression and anxiety in patients with CVA are evaluated, in comparison to patients with classic asthma.¹⁴ The findings of the study were as follows:

• Patients with CVA were on an average more depressed and anxious than classic asthma outpatients.¹⁴
• Mood disorders and anxiety disorders were more common in patients with CVA.¹⁴

Summary

• Cough-variant asthma is one of the most common causes of chronic nonproductive cough in an otherwise healthy patient.⁸
• Absence of dyspnea, dry cough, normal chest findings, and unremarkable chest radiography strongly suggest the diagnosis of CVA.⁸
• Cough-variant asthma responds to bronchodilator and/or steroid inhalation treatment.⁸

References

1.Chest. 2006;129:75–79.

2.J Allergy Clin Immunol Pract. 2014;2(6):671–80.

3.Multidiscip Respir Med. 2010;5(2):99–103

4.J Asthma. 2017;28:1–6

5.J Assoc Physicians India. 2013;61(5l):20–2

6.Indian J Allergy Asthma Immunol. 2011;25(2):85–89

7.Allergol Int. 2014;63:293–333

8.J Enam Med Col. 2013;3(1):29–31

9.Curr Respir Med Rev. 2011;7:47–54

10.Ther Adv Chronic Dis. 2011;2(4):249–64.

11.Singapore Med J. 2016;57(2):60–63.

12.RinshoByori. 2014;62(5):464–70

13.Expert Opin Pharmacother. 2007;8(17):3021-28

14.J Psychosom Res. 2015;79(1):18–26.

Nocturnal Asthma

Nocturnal asthma is described as night-time deterioration of reversible airway disease, along with an increase in symptoms and airway responsiveness.¹ It has been reported that almost 75% of asthmatic patients are aroused by asthma symptoms at least once per week, and nearly 40% experience nocturnal symptoms on a nightly basis.²

Epidemiology        

• Nocturnal asthma has been described to be more prevalent in the elderly population.¹
• In the largest study on the prevalence of nocturnal asthma symptoms involving 7,729 patients with asthma, 74% patients awoke at least once per week with asthma symptoms, 64% patients reported nocturnal asthma symptoms at least 3 times per week, and approximately 40% of patients experienced symptoms nightly.³
• A report on mortality statistics related to asthma revealed that 53% of asthma deaths occurred during night time; 79% of these patients had premortem complaints of asthma disturbing their sleep, and 42% had complaints occurring every night.²

Epidemiology of Nocturnal Asthma: Indian Scenario

• An epidemiological study on bronchial asthma conducted in South India reported the prevalence of nocturnal asthma to be 17.5%.⁴

Definition

Nocturnal asthma is defined as a drop in forced expiratory volume in 1 sec (FEV1) of at least 15% between bedtime and awakening in patients with clinical and physiologic evidence of asthma.²

Etiopathogenesis

Etiology

• The origin of nocturnal asthma is not yet established.
• A circadian rhythm of nocturnal impaired lung function has been noted in patients with asthma, with a nadir at 4 a.m. for all the three characteristic features of asthma-airway obstruction, inflammation, and bronchial hyper-responsiveness.¹

• Multiple factors such as genetic, physical, and environmental characteristics of the patient are believed to play a role.¹
• Contributing factors associated with exacerbation of nocturnal asthma are presented in Figure 1.²

Pathophysiology

• A circadian pattern has been demonstrated for asthma, with the best lung function seen at around 4 p.m., and the worst at around 4 a.m.²
• It is observed that patients with nocturnal asthma have more night-time augmentation of inflammatory cells and mediators, lower levels of epinephrine, and increased vagal tone.⁵
• Though a similar circadian pattern in lung function is also seen in normal population, the peak-to-trough swings in peak expiratory flow rate are more pronounced in asthmatics 15–50% vs. 5– 8%.²
• The pathophysiological effects noted in nocturnal asthma are presented in Box 1.²

Box 1: Pathophysiological effects observed in nocturnal asthma²

• Exacerbation of the effects of normal changes in neurohormonal activation, which have time-related rhythms
• Higher peak levels of corticotropin, without commensurate increase in cortisol levels
• Chronically enhanced inflammatory activity, which in turn diminishes the ability of peripheral blood mononuclear cells to respond further to stimulation at night
• Higher peak melatonin levels, which are associated with a greater overnight fall in lung function
• Enhanced parasympathetic activity
• Inflammation of distal, smaller airways resulting in the loss of the normal volume-resistance coupling of the respiratory system
• Circadian changes in bronchial reactivity, subsequently leading to greater overnight fall in peak expiratory flow rates
• Increased cluster of differentiation CD51 levels, suggesting relationship to the lung inflammatory and repair processes in response to injury
• Increased alveolar tissue CD4+ cells at 4 a.m., as well as increased airway eosinophils, neutrophils, CD4 lymphocytes, superoxide production, and mediators of bronchoconstriction at 4 a.m., as seen in bronchoalveolar lavage
• Increased levels of mast cell mediators such as leukotrienes, interleukins, and histamines at night
• Increased mean exhaled nitric oxide concentrations at all circadian time points
• Increased capillary blood volume during sleep by 16%, thereby recruiting additional inflammatory cells and producing more edema in the airways

Clinical Manifestations

• The distinctive presentation of nocturnal asthma is the occurrence of typical asthma symptoms during the night or in the early morning (Figure 2).²
• The frequency and severity of nocturnal asthma symptoms normally corresponds to daytime asthma symptoms and extent of airflow limitation.²
• Correlation of symptoms in nocturnal asthma with typical asthma is demonstrated in Figure 3.²

Evaluation and Diagnosis

The diagnosis of asthma should be confirmed based on a history of typical, intermittent symptoms of asthma, demonstration of reversible airflow limitation (preferably by spirometry), and exclusion of alternative diagnoses (Figure 4).²

Assessing Gastroesophageal Reflux Disease in Patients with Nocturnal Asthma

• Gastroesophageal reflux disease (GERD) is frequently seen in patients with asthma and it has been recognised as a possible trigger for asthma.²

• The pathophysiologic mechanisms of esophageal acid-induced bronchoconstriction are represented in Figure 5.6,7
• In patients with refractory nocturnal asthma, thorough evaluation, including allergy testing, overnight polysomnography (PSG) and an empiric trial of antigastroesophageal reflux disease therapy may be required.²
• If the patient complains of a sour taste in the mouth upon arising or chest radiograph reveals opacities – which could not otherwise be explained – it is likely that this may be due to reflux with aspiration.²
• Treatment of GERD in patients with nocturnal asthma should be guided by the symptoms of reflux, and not by worsening of asthma.²

Assessing Obstructive Sleep Apnea in Patients with Nocturnal Asthma

• Obstructive sleep apnea (OSA) is a condition involving the upper airways (nasal, oral, and pharyngeal passages), and is characterised by inspiratory flow limitation and repeated airway collapse during sleep. These are associated with many daytime symptoms such as sleepiness, morning headaches, depression, concentration difficulties, and memory loss.⁸
• OSA is more prevalent among patients with severe asthma and is linked to asthma exacerbations and recurrent asthma attacks.⁸
• Coexistence of OSA with asthma can cause deterioration of nocturnal asthma symptoms.²
• OSA can lead to nocturnal awakening and thus should be considered in the differential diagnosis of nocturnal asthma.²
• Functional assessments (bronchial provocation/dilation test) or polysomnography may be of value in differentiating OSA from asthma. In fact, testing for OSA is recommended by the current asthma guidelines in obese or overweight patients with poorly controlled asthma.⁸
• Continuous positive airway pressure (CPAP), the main nonsurgical therapy used for OSA, has been shown to improve asthma symptoms.⁸

Nocturnal Asthma:Effect on Quality of Life

Results of a study, which evaluated sleep quality and daytime cognitive performance in patients with nocturnal asthma, are summarised below.⁹

• Average scores for subjective sleep quality were poorer in asthma patients than in normal subjects.
• Objective overnight sleep quality was also worse in the asthmatic patients compared with normal, healthy subjects.
• Daytime cognitive performance was worse in the patients with nocturnal asthma, even with their usual-maintenance asthma treatment.

Management of nocturnal asthma

The management of nocturnal asthma is shown in Figure 6.

Summary

Objectively, nocturnal asthma is characterised by diurnal decrease in forced expiratory volume in one second (FEV ) of greater than 15%.¹

•   Circadian rhythm has been observed in nocturnal asthma patients with worsening of airway obstruction, inflammation, and bronchial hyper-responsiveness at 4 a.m.¹
•   Evaluation of nocturnal asthma should rule out gastroesophageal reflux disease and obstructive sleep apnea.²

References

1.Mcgill J Med. 2009;12(1):31–38.

2.Glob J Allergy. 2016;2(1):003–009.

3.J Allergy Clin Immunol. 2005;116:1179–186.

4.Indian J Allergy Asthma Immunol. 2011;25(2):85–89.

5.Mt Sinai J Med. 2002;69(3):140–47.

6.Chronobiol Int. 1999;16(5):641–62.

7.Am J Med. 2001;111 Suppl 8A:8S–12S.

8.Chin Med J (Engl). 2015;128(20):2798–804.

9.Thorax. 1991;46(8):569–73.

Exercise-Induced Asthma

Physical exercise  may  induce  symptoms  such  as  cough,  chest  tightness,  and  shortness  of breath in people with asthma that is not adequately controlled; this is often called exercise- induced asthma (EIA).1 Sometimes, people who do not have asthma still experience asthma-like symptoms during exercise, which is called exercise-induced bronchoconstriction (EIB).1 These terminologies are explained in Box 1.²

 Box 1: Terminologies pertaining to exercise-induced asthma (EIA) and exercise-induced bronchoconstriction (EIB) ²

• “EIB with asthma” is used to describe EIB with the presence of clinical symptoms of asthma and “EIB without asthma” is used for an acute airflow obstruction without asthma symptoms, as per the consensus among the American Academy of Allergy, Asthma, and Immunology; the American College of Allergy, Asthma, and Immunology; and the Joint Council of Allergy, Asthma, and Immunology.
• As per the joint task force of European Academy of Allergy and Clinical Immunology and European Respiratory Society, EIB denotes a decrease in lung function after exercise, as observed in exercise test, while EIA refers to symptoms of asthma that occur after exercise.
• The terms EIA and EIB are often used interchangeably.

Epidemiology of EIA

• The prevalence of EIA in adults in the general population ranges between 10% and 20%.³
• A Cochrane review reported the prevalence of EIA to be 5–20% in the general population, to even 100% in subjects with uncontrolled asthma.¹
• In patients with asthma not requiring inhaled corticosteroids, the prevalence was found to be 70–80%, while only 50% of those treated with inhaled corticosteroids had EIA.³
• The prevalence of EIB is reported to be 40% in patients with atopic dermatitis and allergic rhinitis and that of EIA is reported to be 11–50% among elite athletes.^3,4

Definition

Exercise-induced asthma is defined as acute, transient airway narrowing or the transient increase in airway resistance that occurs during or after vigorous exercise.¹ The features of EIA are as follows: ⁵

• · Bronchospasms peaking out 5–10 mins after stopping exercise and resolving in another 20–30 mins
• · A 10–15% decline in forced expiratory volume in the first second of expiration (FEV1) after exercise provocation

Etiopathogenesis

Etiology

Factors contributing to or responsible for EIA are shown in Figure 1.^6,7

Pathophysiology

Two pathophysiological processes have been proposed for EIA (Figure 2) – the water loss theory and the thermal expenditure theory.³ Both result from hyperventilation. The emerging mechanisms of EIB are represented in Figure 3.⁷

Clinical Features

• ·The signs and symptoms of EIA are as follows5:

o   Dyspnea, wheezing, cough, and chest tightness associated with exercise⁵

o   Cough, fatigue, below-par performance on the field of play, gastrointestinal discomfort, prolonged recovery time⁶

• ·Symptoms are triggered by 6–15 mins of continuous exercise of at least 80% maximum workload.⁵

Differential Diagnosis

• The differential diagnoses for EIA include chronic asthma (chronic lung diseases), exercise- induced vocal cord dysfunction, exercise-induced arterial hypoxemia, exercise-induced hyperventilation, and exercise-induced anaphylaxis (Table 1).^2,5
• Other conditions to rule out EIA include bronchitis, anemia, inadequate conditioning, panic disorder, foreign body, cystic fibrosis, alpha-1 antitrypsin deficiency, and previously undiagnosed heart disease.⁵

Diagnosis and Management

Box 2: Diagnostic considerations for exercise-induced bronchoconstriction (EIB) ⁸

• The diagnosis of EIB is determined by changes in lung function triggered by exercise, not based on symptoms
• The percentage of the pre-exercise value refers to the difference between the pre-exercise FEV value and the lowest FEV1 value recorded within 30 mins after exercise. EIB is diagnosed when the criterion for the percentage fall in FEV1 is ≥10%
• Severity of EIB based on percentage fall in FEV  from pre-exercise level: 10%≤ mild <25, 25%≤ moderate <50%,
• and severe ≥50%
• Surrogates for exercise challenge: Eucapnic voluntary hyperpnea or hyperventilation, hyperosmolar aerosols, and dry powder mannitol

Box 3: Summary of leukotriene receptor antagonists (LTRA) in the management of EIA⁵

• As LTRAs are available in an oral formulation, they may be useful in patients who have difficulty inhaling
• Leukotriene receptor antagonist therapy appeared to be more effective than monotherapy with a long-acting β2-agonist, and may have a synergistic effect with short-acting β2-agonists
• Montelukast 10 mg 2 h before exercise in patients <15 years was found to control EIA
• In one of the studies, montelukast therapy provided significantly greater protection against EIA than placebo and was associated with a significant improvement in the maximal decrease in FEV1 after exercise

Summary

•     Exercise-induced asthma is a treatable disorder, but remains undiagnosed by clinicians.⁵
•     Exercise challenge is an important step in the diagnosis EIA.⁸
•     The pharmacologic treatment options include SABAs, LABAs, anticholinergic, ICS, LABAs, and LTRA.⁸

References

1. The Cochrane Library. 2013;10.

2. Front. Pediatr. 2017;5(131). Available from: doi: 10.3389/fped.2017.00131.

3. Curr Sports Med Rep. 2018;17(3):85–89.

4. J Asthma. 2012;49(5):480–86.

5.  J Am Acad Physician Assist. 2011;24(6):26–30.

6. Malays Fam Physician. 2008;3(1):21–24.

7. Allergy. 2018;73:8–16.

8. Am J Respi rCrit Care Med. 2013;187(9):1016–27.