Bronchial challenge test in patients with a history suggestive of bronchial asthma with normal spirometric studies

Abstract

Background

Bronchial hyper-responsiveness (BHR) is the hallmark of bronchial asthma, characterized by clinical features of cough, wheeze, breathlessness and chest tightness which are confirmed by spirometry showing obstructive pattern and reversibility to bronchodilators. In individuals having features of bronchial asthma but normal spirometry, demonstration of BHR with bronchial challenge test (direct or indirect) confirms/ rules out the diagnosis. The aim of this study was to assess BHR in patients (methacholine challenge) with a history suggestive of bronchial asthma but normal spirometry and its role in diagnosis of bronchial asthma.

Methods

This study was conducted at tertiary care respiratory center. Patients having clinical features of bronchial asthma but spirometry not confirming obstructive disorder and or reversibility were included in the study. After written consent, methacholine challenge test with methacholine chloride and exercise spirometry was done in all patients as per the American Thoracic Society protocol.

Results

A total of 50 (n) patients were included in the study. Among them, 42 patients had clinical features suggestive of bronchial asthma but having normal spirometry and eight patients were diagnosed as they had bronchial asthma in the past but asymptomatic and off drugs were included in the study. At PC20 4mg/ml 32 (64%) patients had a positive test, 28(66%) symptomatic patients and four (50%) asymptomatic asthmatics. There were no significant side effects with methacholine test.

Conclusion

Airway hyper-responsiveness is an important aspect of bronchial asthma and its demonstration with bronchial challenge (direct and indirect) test is an important diagnostic tool. Methacholine challenge test is a safe procedure to perform under supervision.

Introduction

Bronchial asthma is a chronic inflammatory disorder characterized by airway hyper-responsiveness, which is typically characterized by episodic wheezing, breathlessness, chest tightness and spasmodic coughing.¹ These episodes of variable outflow obstruction are generally reversible, either spontaneously or with treatment. The gold standard for the diagnosis of asthma is the demonstration of reversible airway obstruction on spirometry (increase in forced expiratory volume in 1 s [FEV1] >12% and 200 ml from baseline, 10–15 min after 200–400 mcg of rapid-acting inhaled bronchodilator like salbutamol or an equivalent given through a metered dose inhaler). Occasionally, a patient with a suspected asthma-related airway obstruction does not demonstrate obstruction or reversibility on spirometry (in between symptoms, the patient has used beta2-agonist within few hours of testing, and in some patients, airflow obstruction may become irreversible over time).²

Bronchial hyper-responsiveness (BHR) demonstrated that inhaled bronchospastic agents help to confirm the diagnosis of bronchial asthma. Bronchoprovocative test can be direct or indirect test. The direct test includes nonspecific pharmacological agents such as methacholine and histamine, whereas indirect test stimuli include exercise, voluntary hyperventilation, cold air hyperventilation, hypertonic saline, mannitol and adenosine monophosphate. Bronchial challenge tests are easily performed in adults and children aged more than 7 years.^{3, 4, 5}

This study was conducted with an aim to asses BHR in patients with a history suggestive of bronchial asthma with normal spirometry test in hospital settings.

Materials and method

The study was conducted from June 2008 to June 2010. Patients reporting to the chest OPD directly or after referral with symptoms suggestive of bronchial asthma were subjected to spirometry.

Inclusion criteria

• 1.Individuals with classical symptoms of bronchial asthma, cough, wheeze, breathlessness and chest tightness, but not having spirometry findings to confirm asthma.
• 2.Individuals having symptoms at work places such as ship engine room or in AC environment, but were asymptomatic in a hospital environment.
• 3.Personals diagnosed as asthmatic based on a single episode of wheeze and breathlessness and having BHR, but asymptomatic thereafter without any medication.

Exclusion criteria

The patients meeting inclusion criteria, but having any of the following were excluded:

• 1.Severe airflow limitation (FEV1 ≤50% predicted or, ≤1.0 l).

• 2.Myocardial infarction or cerebrovascular disease in the last 3 months.

• 3.Uncontrolled hypertension, systolic BP ≥ 200 mm Hg or diastolic BP ≥ 100 mm Hg.

• 4.Inability to perform spirometry of acceptable quality.

• 5.Pregnancy.

• 6.Current use of cholinesterase inhibitor medication (for myasthenia gravis).

Dosing protocols

We used a five-breath dosimeter protocol. We used KOKO DigiDoser, which is a KOKO PFT Spirometer with built-in dosimeter manufactured by nSpire Health, Inc., 1830 Lefthand Circle, Longmont, CO 80501. It meets all the standards laid down by ATS guidelines.

The following five concentrations of methacholine were prepared in sterile vials and stored in a refrigerator.

Diluent: 0.0625, 0.25, 1, 4, 8 and 16 mg/ml.

Patients were nebulized initially with saline, five doses of saline were given and spirometry performed at 30 and 90 s after the 5th dose. Thereafter, methacholine is nebulized, starting from the lowest concentration, that is, 0.0625 (five breaths) and spirometry performed as per schedule. If a fall in FEV1 is less than 20%, then the next higher dose is given to the patient. The dose at which FEV1 falls >20% of baseline FEV1 (PC20) or dose of 16 mg/ml is reached, the test is stopped and the patient is nebulized with 5 mg salbutamol.(Table 1)

Table 1.

Bronchial responsiveness was categorized as under.

>16	Normal bronchial responsiveness
4.0–8.0	Borderline BHR
1.0–4.0	Mild BHR (positive test)
<1	Moderate-to-severe BHR

Exercise spirometry

Protocol

Treadmill was used for exercise. Speed and grade of the exercise were gradually increased to achieve target heart rate, which is 80–90% of maximum heart rate predicted for age of the individual (predicted maximum heart rate is calculated as 220 minus age in years), and individual exercises for 3–4 min after achieving target heart rate. Spirometry is performed in the seated position before exercise and then serially after exercise, 5, 15 and 30 min after cessation of exercise. Two to three acceptable tests are performed at each testing interval and the best is recorded. Symptomatic patients were given bronchodilators.

Results

The study included 50 patients meeting inclusion criteria and was conducted from June 2008 to June 2010. The average age of the patients was 22–52 years. Forty-six patients were male and four patients were female.

A total of 42 patients were having symptoms of cough, wheeze, breathlessness and chest tightness suggestive of bronchial asthma, episodic in nature and spirometry was not confirming the obstructive airway disease and reversibility. Eight patients were diagnosed as asthmatic or had symptoms in the past, but were off drugs and were asymptomatic for at least 1 year at the time of study.

Positive result PC20

• 1.PC20 of 4 mg/ml or less was taken as positive for BHR in this study.

• 2.32 (64%) patients were found to be positive for methacholine challenge, that is, PC20 was achieved at 4 mg/ml, 28 (62%) of symptomatic and four (50%) of asymptomatic asthmatic patients were positive.

• 3.Further analysis of the data showed that a fall in FEV1 of more than 20% was achieved in 12 patients at a concentration of 1 mg/ml of methacholine inhalation and in 40 patients at 16 mg/ml concentration.

Exercise spirometry was performed in all the cases, and it showed a 15% fall in FEV1 in most of the cases who were positive on methacholine challenge of 4 mg/ml. However, three patients were found to be negative on methacholine challenge but were positive for BHR on exercise spirometry, two of them had hyper-responsiveness to methacholine at 8 mg/ml. The following symptoms were observed in patients during the study: Nil—70%, Cough—25%, Dyspnoea—21%, Wheeze—10% and Headache—2%.

Discussion

In this study, we included 50 patients having clinical features of bronchial asthma, but spirometry did not confirm the diagnosis (reversible obstructive disorder). All the patients were subjected to bronchial challenge test with methacholine and exercise test as per the American Thoracic Society protocol.

Out of 50 (n) patients, 46 were male, most of the patients were in their 2nd to 4th decade. Forty-two patients were having symptoms suggestive of bronchial asthma, but the diagnosis was not confirmed with spirometry, and eight patients were labelled as cases of asthma but were asymptomatic with normal spirometry.

Among 42 patients who had symptoms of asthma, 28 (62%) were found to be positive at PC20 of 4 mg/ml and 36 (85%) at PC20 of 16 mg/ml. Many studies report that airway hyper-responsiveness, as measured by a methacholine PC20, is consistent and reproducible in asthmatics; however, these studies largely evaluated patients with stable asthma.

In asthmatic subjects, there is wide variability in the perception of symptoms and they do not correlate well with objective measurement.⁶ Moreover, the correlation is worst among those with severe asthma.⁷ The following clinical settings are examples of situations in which a patient may report a convincing history of asthma but have a negative challenge.

• 1.Vocal cord dysfunction may result in symptoms suggestive of asthma, but a negative challenge test result. This condition is often detected by careful inspection of the inspiratory flow–volume relationship.

• 2.Central airway obstruction by a tumour, polyp or foreign body can also mimic asthma symptomatically, but results in a negative methacholine challenge.

Eight patients who were asymptomatic at the time of test, but labelled as asthmatic in the past, four (50%) were positive at methacholine inhalation of 4 mg/ml. This can be explained as patients with mild intermittent asthma sometimes are “poor perceiver” of asthma symptoms or they have subclinical bronchial asthma that will become clinical asthma in the future.^8,9 Patients who are asymptomatic but have BHR, 15% and 45%, may have clinical asthma in 2–3 years of follow-up.^10,11 However, patients who were asymptomatic and had the negative methacholine challenge are the individuals who do not have asthma because methacholine challenge test has a very high negative predictive value. A negative methacholine challenge test literally rules out bronchial asthma, in a patient with chronic cough, given the high specificity of this test.^12,13

Three patients were positive on exercise testing but showed no hyper-responsiveness to methacholine challenge of 4 mg/ml. These individuals may be having exercise-induced BHR (EIB), which is not picked up by methacholine challenge. A study performed on 802 Australian schoolchildren showed that although 19% had significant EIB, up to 43% were not asthmatic. Thirty-six children underwent both exercise and histamine tests. Eighteen children had EIB of a severity consistent with a diagnosis of active asthma but were negative to bronchial challenge test with histamine.¹⁴

The methacholine challenge test is being performed routinely in the tertiary care respiratory centre, with no reported serious side-effects. Transient symptoms such as wheeze, cough, mild dyspnoea and chest tightness are common in patients with BHR. In our study, most patients did not experience any side-effects (70%). Minor side-effects were experienced by some of the patients. These side-effects were also experienced in other studies. Delayed or prolonged responses to methacholine are rare. One study reported prolonged responses to high dose of methacholine in four to six adult patients with asthma.¹⁵ However, no prolonged effects were seen in our study.

Conclusion

• 1.The history of cough, wheeze, breathlessness and chest tightness supports and suggest the diagnosis of bronchial asthma, and spirometry confirms it in most of the cases. The bronchial challenge is a useful diagnostic tool in cases where spirometry is normal.

• 2.The high negative predictive value of the methacholine challenge test is of immense value in ruling out the suspicion of bronchial asthma in patients having had a transitory period of BHR.

• 3.It has an important role in the diagnosis of asthma/mild intermittent asthma in recruitment into high-risk trade such as navy divers, air crew and submariners.

• 4.Methacholine challenge is a safe procedure to do in a well-equipped respiratory laboratory with trained staff.

• 5.The only problem with the methacholine challenge test is difficulty in procuring Provocholine (methacholine hydrochloride) as it is not available in Indian market and has to be imported.

Disclosure of competing interest

The author has none to declare.