interpretation of the “positive” methacholine challenge

AMERICAN JOURNAL OF INDUSTRIAL MEDICINE 51:769–781 (2008)

Review

Interpretation of the ‘‘Positive’’Methacholine Challenge

David J. Hewitt, MD, MPH�

Background A methacholine challenge may be used in confirming the diagnosis ofasthma, occupational asthma, or reactive airways dysfunction syndrome (RADS) throughidentification of bronchial hyperreactivity (BHR). While sensitivity of the test indiagnosing clinically significant asthma is excellent, specificity of the test is poor. Sincethere are many conditions which have been associated with BHR, a positive test must beinterpreted cautiously.Methods This paper reviews potential causes of a positive methacholine challenge otherthan asthma or RADS which have been reported in the medical literature.Results Factors which may be associated with a positive methacholine test include testmethodology, normal variation of BHR in the general population, and numerous medicalconditions.Conclusions In cases of inhalation exposure evaluations, alternative explanations mustbe considered when determining whether a causal association exists between the exposureand a positive methacholine test result. Am. J. Ind. Med. 51:769–781, 2008.� 2008 Wiley-Liss, Inc.

KEY WORDS: methacholine; bronchoprovocation; asthma; occupational asthma;reactive airways dysfunction syndrome (RADS)

INTRODUCTION

A methacholine challenge may be used in confirming the

diagnosis of asthma, occupational asthma, or reactive

airways dysfunction syndrome (RADS). For the occupa-

tional medicine physician, it may be considered a primary

determinant in the confirmation of an asthma-like condition

in worker compensation claims. Indeed, one of the listed

criteria for RADS is non-specific bronchial hyper-reactivity

as demonstrated by a positive methacholine challenge

test [Brooks et al., 1985]. In occupational asthma cases,

substance-specific airway challenges provide the best

evidence of a work-related association between a suspected

exposure and respiratory symptoms. However, specific

challenges may not be readily available in the clinical

setting. In such cases, the methacholine challenge may be

used to confirm if a condition of increased airway reactivity is

present. A negative methacholine challenge shortly after a

work shift has been noted to virtually exclude a diagnosis of

occupational asthma [Vandenplas and Malo, 1997].

With the exception of certain types of occupational

asthma such as that from isocyanates in which a methacho-

line challenge can be negative if conducted long after

removal from exposure, the test is considered to have

excellent sensitivity for diagnosing asthma, meaning that

nearly all individuals who have significant asthma will react

to a relatively low methacholine dose. However, because a

number of other factors are associated with increased

sensitivity to methacholine, the specificity or positive

predictive value of the test is poor. Thus, a ‘‘positive’’ test

does not necessarily mean an individual has asthma or other

significant respiratory conditions and must be interpreted

� 2008Wiley-Liss, Inc.

Center forToxicology and Environmental Health, L.L.C., North Little Rock, Arkansas*Correspondence to: David J. Hewitt, 5120 North Shore Drive, North Little Rock, AR 72118.

E-mail: [email protected]

Accepted 25 June 2008DOI 10.1002/ajim.20631. Published online in Wiley InterScience

(www.interscience.wiley.com)

carefully. Misinterpretation of positive test results can have

significant consequences to the affected worker in terms of

future employment, job duties, and health claims. This

review examines potential causes of a positive methacholine

challenge other than asthma or RADS.

METHACHOLINE CHALLENGETESTING METHODS

Methacholine is a cholinergic agonist which provokes

bronchoconstriction when inhaled. The test is typically

performed by having an individual inhale an aerosolized

mist containing methacholine at increasing concentrations

through a nebulizer. The response to methacholine is

measured by performing a pulmonary function test (PFT)

after each dose. The primary PFT measure of interest is the

forced expiratory volume in 1 s (FEV1). If the respiratory

airways are narrowed, such as in an asthma attack, the FEV1

will be reduced and may be interpreted as obstruction.

Most individuals will show some bronchoconstriction at

sufficient doses of inhaled methacholine with associated

decreases in the FEV1 [Townley et al., 1975; Enarson et al.,

1987]. However, individuals with conditions such as asthma

will show a greater decrease in FEV1 to inhaled methacholine

and at much lower concentrations. The degree of reactivity

thereby can also provide a relative index of severity for

an asthma-like condition. A methacholine challenge test is

interpreted as ‘‘positive’’ or showing ‘‘bronchial hyper-

reactivity’’ (BHR) if an individual shows a greater than

expected decrease in the FEV1 after inhaling the methacho-

line solution.

Although bronchoprovocation testing with methacho-

line has been used for several decades in assessing asthma,

review of the medical literature indicates that a number of

different protocols have been used to perform and interpret

methacholine challenge tests. These protocols have differed

in the methods of administration of methacholine, the

concentrations used, and the criteria used for interpreting

the test as positive.

Currently recommended protocols for methacholine

challenge testing have been reviewed in detail [Crapo et al.,

2000]. In short, methacholine may be administered using a

5-breath technique in which the individual takes 5 deep

breaths of each methacholine concentration from a nebulizer

and then performs a PFTafter each dose. Alternatively, a tidal

volume method may be used in which the individual inhales

the methacholine concentration over 2-min while breathing

normally from a nebulizer and then performs the PFT after

each concentration.

The methacholine concentrations used in these tests may

vary significantly depending on the individual study proto-

cols. Typical methacholine concentrations used in the five-

breath method are 0.025, 0.25, 2.5, 10, and 25 mg/ml. The

tidal volume method may use methacholine concentrations

of 0.0625, 0.25, 1, 4, and 16 mg/ml. In older studies, higher

concentrations in excess of 100 mg/ml have been used [Malo

et al., 1983]. The FEV1 is measured shortly after the

inhalation of each concentration is completed. The test is

stopped if the FEV1 decreases 20% or more from base-

line and the corresponding methacholine concentration is

recorded (i.e., the provocative concentration or ‘‘PC20’’).

The test is considered negative if the FEV1 does not decrease

by 20% at the maximum concentration.

Criteria for interpretation of the test are most often based

on the PC20 dose. The exact level between whether a test is

‘‘positive’’ (i.e., showing BHR) or ‘‘negative’’ has varied

between studies but is often defined as a PC20 �8 mg/ml or

�16 mg/ml. PC20 levels of 4–16 mg/ml may be considered

as showing borderline BHR [Crapo et al., 2000]. Individuals

with significant asthma often react at a PC20 <1 mg/ml

which is consistent with moderate to severe BHR. The

probability that an individual has true asthma increases

substantially with lower PC20 levels.

Methacholine challenge testing may also be performed

using plethysmography in which airway conductance and

resistance are measured. Interpretation of plethysmography

results is more difficult since airway conductance and

resistance are more variable than changes in FEV1 and there

are relatively few published studies of BHR for comparison

using this method.

POTENTIAL CAUSES OF A POSITIVEMETHACHOLINE CHALLENGE

The prevalence of asthma in U.S. adults has been

estimated as approximately 7% [Drezen, 2008]. However,

population surveys using methacholine challenges typically

show positive rates significantly higher than 7% indicating

that other factors are associated with a positive result. As

summarized in Table I and reviewed below, these factors may

include testing techniques, normal background variation, and

various medical conditions.

Because there are different methods of performing

bronchoprovocation testing, there may be limitations in

directly comparing study results. For instance, methacholine

results may be expressed as either the PC20 or as the

provocative dose (PD20), which is the cumulative dose of

methacholine which caused a 20% decrease in FEV1. There

has been debate about whether the methacholine concen-

tration or dose is the more important factor in causing a

response [Kleerup and Tashkin, 1997; Drotar et al., 1999].

Some studies have been based on plethysmography measure-

ments rather than spirometry. Histamine has been used in

the past for evaluation of BHR and has been noted to

have a similar dose-response relationship to methacholine

[Hargreave et al., 1981]. However, histamine is associat-

ed with more side-effects and there are relatively few

published studies of bronchoprovocation using histamine.

770 Hewitt

For comparability, this review is limited mainly to studies in

which methacholine was used and the results expressed as a

PC20 when possible.

Technical Factors Which May AffectMethacholine Challenge Testing

As with any medical test, a number of technical factors

can affect the reliability of methacholine challenge testing.

Methacholine is supplied as a dry crystalline powder which

must be solubilized using normal saline prior to use. Accurate

sterile mixing is required in order to produce the referenced

methacholine concentrations. Package insert information

recommends that the solution for the lowest dose be mixed on

the day of testing and that the solutions not be stored for more

than 2 weeks [Mosby’s, 2007]. Contamination or improper

dilution preparation may affect the irritant potential of the

administered solutions and the reproducibility of results.

The amount of delivered solution during the test also is a

consideration in interpreting results. Factors which may

affect the amount of delivered solution include the temper-

ature of the testing environment and performance of the

individual nebulizer. Kongerud et al. [1989] noted that the

output from the type of nebulizer used in methacholine

challenge testing may increase by 23% when the room

temperature was increased from 19 to 248C. Specific types of

nebulizers have been recommended for performance of the

test and are designed to generate a specific amount of

methacholine aerosol with a consistent particle size [Crapo

et al., 2000]. However, nebulizer output theoretically may

vary from model to model, from unit to unit, or may vary

with time depending on maintenance and cleaning of

nebulizers if they are reused.

TABLE I. Potential Factors Associated With a Positive MethacholineChallengeTest

Condition Specific factors

Technical Improperly prepared solutionImproper solution storageContamination of solutionTemperatureNebulizer performanceBreathing techniquePatient effortTesting operator techniqueInterpretation criteria

Normal variation Background rate in asymptomatic individualsGender (female)Baseline airway caliberAgeAnnual or seasonal variabilitySuggestion

Allergy Allergic and non-allergic rhinitisGeneral atopyDust mite or cat allergyFood allergy

Respiratory infection Common coldInfluenzaCroupSinusitisMycoplasma pneumoniaTuberculosis

Smoking Current smokersEx-smokersPassive cigarette smoke exposure

Chronic respiratory conditions BronchitisBronchiectasisChronic obstructive pulmonary disease

Cardiovascular conditions Mitral valve stenosisCongestive heart failureVasospastic anginaC-reactive protein (CRP)Carotid intima thickness

Gastrointestinal conditions Irritable bowel syndromeCrohn’s diseaseUlcerative colitisGastroesophageal reflux

Autoimmune disorders Rheumatoid arthritisSjogren’s syndromeSarcoidosis

Athletes Hockey playersSkiersSwimmersFootball players

Miscellaneous Antishock trousersHistory of childhood asthmaChronic lymphocytic leukemiaCoal minersDietary factorsEndotoxinsFirefightersGas cookingHIVInhalational drug abuseMastocytosisObesityPerinatal respiratory infectionPig farmingSpinal cord injuryVocal cord dysfunction

TABLE I. (Continued )

Condition Specific factors

Methacholine Challenge Interpretation 771

A third technical factor is patient effort and technique.

The dose of methacholine delivered can be affected by the

rate of inhalation and depth of inhalation. For example,

individuals with submaximal inhalation actually may respond

to lower doses of methacholine than if they had used deep

inspiratory maneuvers [Brown et al., 2000]. A proposed

mechanism is that deep inspiration may cause smooth muscle

relaxation and bronchodilation.

Because the test is based on PFT results, it is necessarily

effort-dependent and relies on the tested individual to

produce their best effort. Poor effort due to poor instruction

on the test, motivation, or coughing during the PFT may

result in a decreased FEV1 and erroneous results. As with

any PFT, flow-volume loops may assist in evaluating the

validity and reliability of PFT’s obtained during a methacho-

line challenge. The expertise and experience of individuals

administering the methacholine challenge can be a signifi-

cant factor in obtaining valid testing results.

Response to methacholine also may naturally vary from

year-to-year possibly due to factors such as environmental

effects, normal physiologic variation, or differences in test

methods. Beckett et al. [1997] examined methacholine

responses among a group of 105 nonasthmatic adults at

1 year intervals for up to 4 years. At least 30% of the parti-

cipants had an annual change in methacholine responsive-

ness of one or more doubling doses.

Simple suggestion also may cause an increase in airway

reactivity. Spector et al. [1976] conducted a study in which

volunteers were told prior to testing that a flavored diluent

without bronchoconstrictor effects was either a bronchocon-

strictor or a bronchodilator and compared the results to

earlier testing in which they were not told this information.

The decrease related to suggestion was intermediate between

that produced by methacholine and control solutions.

Normal Variation

The background prevalence of positive methacholine

challenge tests identified in the general population with no

history of asthma have ranged from<10 to>40% depending

on selection and interpretive criteria as shown in Table II

[Malo et al., 1983; Weiler et al., 1986; Casale et al., 1988;

Trigg et al., 1990; Hassan et al., 1994; Louis et al., 1995;

Chinn et al., 1997; Leynaert et al., 1997; Wassmer et al.,

1997; Chowgule et al., 1998; Gulec et al., 1999; Bagnato

et al., 2000; Langdeau et al., 2000; Poirier et al., 2001;

Roth et al., 2001; Schwartz et al., 2002; Petays et al., 2003;

Jayet et al., 2005]. In the largest of the general population

prevalence studies which included over 13,000 participants

in the European Community Respiratory Health Survey

(ECRHS), the prevalence of BHR ranged from 3% to 28%

among testing centers in 16 countries with a median

prevalence of 13% [Chinn et al., 1997]. Even studies of

selected populations with no known history of common

causes of a positive methacholine challenge test such as

asthma, rhinitis, allergies, or recent respiratory illness have

reported BHR rates ranging up to 28% [Malo et al., 1983;

Casale et al., 1988; Roth et al., 2001; Jayet et al., 2005]. Thus,

a positive result may have little clinical significance.

Background prevalence rates of BHR within populations

may further be affected by the gender and age distribution of

the study population. The prevalence of BHR in females is

generally 2–3 times higher than that in males in studies

in which stratification by gender was reported. A possible

explanation is related to differences in baseline airway

caliber (i.e., asymptomatic individuals with lower baseline

airway calibers may be more likely to have a positive res-

ponse to methacholine due to anatomical differences alone).

As evidence, Bourbeau et al. [1993] noted a significant

difference in response to methacholine among a sample of

male construction workers based on tracheal length and

diameter assessed from chest X rays. They suggested that

decreased tracheal size may result in an increase in airway

response to methacholine due to increased deposition

secondary to smaller cross-sectional area of the airway.

Some studies have suggested that methacholine respon-

siveness increases with increasing age. Wassmer et al. [1997]

reported the prevalence of BHR in men and women was

highest in the 55–64 year age group (34.5% and 21.9%

for females and males respectively). Prevalence in other

age groups ranged from 8.5% to 29.3%. Rijcken et al.

[1987] noted that BHR to histamine in a group of over

500 nonsmokers progressively increased from 10.9% in

those aged 14–24 to 42.9% in those age 55–64.

Medical Conditions AffectingMethacholine Challenge Testing

Assuming that a positive methacholine challenge test

result is not secondary to technical factors or normal

variation, the clinician must then determine whether their

patient has any underlying medical conditions other than

asthma which could cause a positive test result. The number

of medical conditions or other factors other than asthma

which have been identified with increased rates of BHR is

surprisingly large (Table III). Several of the more commonly

identified conditions are reviewed below.

Allergic conditions

Allergic rhinitis has been estimated to affect up to 40%

of the general population [Ciprandi et al., 2004b]. Studies

consistently find a strong association between BHR and

a history of either allergic or nonallergic rhinitis with

prevalence rates sometimes in excess of 50% [Ramsdale

et al., 1985; Prieto and Marin, 1990; Prieto et al., 1994; Leone

et al., 1997; Okayama et al., 1998; Jang, 2002; Ciprandi et al.,

2004a,b; Di Lorenzo et al., 2005]. BHR appears to increase

772 Hewitt

with exposure to the offending allergen (i.e., during ‘‘pollen

season’’) but is also present during the seasons when the

individual is presumably not being exposed to the allergen

[Ciprandi et al., 2004a,b; Di Lorenzo et al., 2005]. In

addition, BHR may be provoked by direct allergen contact

and can last for weeks after the initial allergic inflammation

has resolved [Dreborg, 1996].

Several studies have shown a specific association of

BHR with sensitivity to dust mites, cats, and timothy grass

[Chinn et al., 1999; Ernst et al., 2002; Wong et al., 2002;

Kerkhof et al., 2003]. Interestingly, food allergies have also

been associated with increased BHR with reported preva-

lence rates in excess of 50% in nonasthmatic individuals

[Thaminy et al., 2000; Wallaert et al., 2002].

Respiratory infections

Upper respiratory viral infections such as influenza,

viruses producing the common cold, and others may result

in increased bronchial responsiveness to methacholine

TABLE II. Background BHR Rates

BHRRate BHR criteriaa Study population References

Background ratesAselected samples with no history of conditions commonly associated with BHR3% 8 100 adults age 20^60 with no history of smoking, cough, asthma, family history of

asthma, rhinitis, atopy, or recent upper respiratory illnessMalo et al. [1983]

8% 162% 2.5 50 non-smoking adults age 18^ 35 with no history of allergy, asthma, rhinitis, or

recent respiratory infectionsCasale et al. [1988]

6% 5.010% 10.028% 25.03% 2.5 63 ROTC students age18 ^31with no history of asthma Roth et al. [2001]10% 1013% 2511% 25 1,567 adults with no history of smoking, asthma, atopy, or recent respiratory

infection; rate in males 4% versus15% in femalesJayet et al. [2005]

23% 2 318 patients age 18^75 from physician general practice survey; rate in males 13%versus 31% in females

Trigg et al. [1990]

Background ratesAgeneral population surveys13% (median) 12.5 13,161randomly selected individuals age 20^44, tested at 35 locations in

16 countries (range of 3^ 28% for different testing centers)Chinn et al. [1997]

12% 25 799 randomly selected French adults from Paris and Montpelier age 20^ 44;rate12^ 30% in males; 34^43% in females

Leynaert et al. [1997]

13% males 12.5 931randomly selected German adults age 20^65 Wassmer et al. [1997]28% females14% 12.5 516 randomly selected Indian adults age 20^ 44 Chowgule et al. [1998]12% males 25 7,126 randomly selected Swiss adults age18 ^60 Schwartz et al. [2002]22% females14% 25 888 randomly selected Finns and Russians age 25^54 Petays et al. [2003]

Background ratesAcontrol populations from other studies41% 25 167 medical and physician assistant students, students with overt asthma excluded Weiler et al. [1986]20% 100 41adult non-smokers Hudgel and Roe [1988]16% 32 50 adults with minor degenerative joint problems in rheumatoid arthritis study Hassan et al. [1994]17% 16 24 adults age 22^40 in study of inflammatory bowel disease Louis et al. [1995]0% 8 28 physicians who had no history of recent smoking, asthma, or respiratory infection Gulec et al. [1999]7% 8 30 adults age18 ^49 with no history of asthma, smoking, or airborne allergies Bagnato et al. [2000]28% 16 50 adults with no history of smoking or recent respiratory infection Langdeau et al. [2000]14% 12.5 236 adult males age 20^44 Poirier et al. [2001]

BHR, bronchial hyperreactivity.aBHR criteriaAcited methacholine concentration (mg/ml) causing a 20% decrease in FEV1 (i.e., PC20). In those cases where a provocative dose (PD) was reported, the PC20 wasinterpreted as the maximum methacholine concentration corresponding to the PD.


TABLE III. Conditions Associated With Increased BHR Rates

Condition BHR rate BHR criteriaa Study population References

AllergyFood allergy 53% 8 19 adults with food allergy and no history of asthma or rhinitis Thaminy et al. [2000]Food allergy 50% 16 12 adults with food allergy and no history of asthma or rhinitis Wallaert et al. [2002]Allergic rhinitis 32% 18 73 adults with allergic rhinitis, nonsmokers and no asthma Prieto et al. [1994]Allergic rhinitis 78% 25 40 adults with allergic rhinitis, no chronic sinusitis, and nonsmokers,

tested using plethysmography and decrease in conductance of 35%Okayama et al. [1998]

Allergic rhinitis 63% 25 35 adults with allergic rhinitis, no history of asthma, eosinophilia, or recentrespiratory infections

Jang [2002]

Allergic rhinitis 76% NR 95 adults with perennial allergic rhinitis, non smokers; maximumlisted methacholine concentration reported as 0.34 mg/ml

Ciprandi et al. [2004a]

Allergic rhinitis 54^56% NR 100 adults with seasonal allergic rhinitis; seasonal allergic patients testedboth during (56% positive) and outside (54% positive) of pollen season;maximum listed methacholine concentration reported as 0.34 mg/ml

Ciprandi et al. [2004b]

Allergic and nonallergicrhinitis

39% NR 410 adult rhinitis patients without asthma or recent respiratory infection Di Lorenzo et al. [2005]

Nonallergic rhinitis 46% NR 39 adults with nonallergic rhinitis and no history of asthma Leone et al. [1997]Sinusitis

Chronic sinusitis 43% 8 106 adults with chronic sinusitis exacerbation and no history of asthma,PC20 based on histamine challenge

Bucca et al. [1995]

Chronic sinusitis 71% 25 42 adults with chronic sinusitis and no allergic rhinitis or asthma; testedusing plethysmography and decrease in conductance of 35%

Okayama et al. [1998]

SmokingSmoking 35% 25 46 adult smokers age 18 ^35 with no history of asthma, rhinitis, allergic

disease, or recent respiratory infectionsCasale et al. [1987]

Smoking 58% 25 65 male smokers age 21 ^80 with no history of asthma, rate in 161 neversmokers and 232 former smokers was 23 and 27%, respectively

Sparrow et al. [1987]

Smoking 24% females 100 558 adults age 20 ^44, current smokers with no atopy Sunyer et al. [1997]18% males

BronchitisChronic bronchitis 100% NR 22 adults with chronic obstructive bronchitis and no history of asthma

or allergic disease, BHR determined with plethysmography, all patientsvery sensitive to methacholine, average PC was 0.31 ^0.62 mg/ml

Ramsdell et al. [1982]

Chronic bronchitis 64% 16 28 adults with chronic bronchitis, all were current or past smokers Bahous et al. [1984a]Chronic bronchitis 70% 8 27 adults with chronic bronchitis patients, all with smoking history Ramsdale et al. [1984]Chronic bronchitis 58% 25 50 adults with simple chronic bronchitis and no airway obstruction;

tested using plethysmography and decrease in conductance of 35%Okayama et al. [1998]

COPD 46% NR 59 adults with COPD and no history of asthma or current use ofasthma medications, BHR assessed using histamine

Yan et al. [1985]

Other respiratory infectionsMycoplasma pneumonia 67% 25 12 adults tested 4 weeks after mycoplasma pneumonia infection; 50% still

positive at 12 weeks; all were nonsmokers with no history of asthma orallergic disease

Wongtim and Mogmued[1995]

Croup 80% NR 10 children with history of recurrent croup and no history of asthma Litmanovitch et al.[1990]

Tuberculosis 28% 25 18 adults with active tuberculosis Park et al. [1989]Bronchiectasis 69% 16 29 adults with chronic bronchiectasis Bahous et al. [1984b]Bronchiectasis 20% NR 30 adults with bronchiectasis Pang et al. [1989]Bronchiectasis 45% 8 47 adults with bronchiectasis, no other selection criteria Ip et al. [1991]

774 Hewitt

for weeks after recovery. A high percentage of BHR has been

noted in children with a history of recurrent croup

[Litmanovitch et al., 1990]. It has been suggested that the

viruses can damage the airway epithelium which makes it

more sensitive to irritants [Wennergren, 1996]. Empey et al.

[1976] concluded that viral upper respiratory tract infections

cause increased bronchial reactivity which is present during

infection and for several weeks after recovery and may be

related to damage to the airway epithelium.

Increased bronchial reactivity has been reported among

individuals who were voluntarily exposed to influenza virus.

Hobbins et al. [1982] reported a trend toward increased

bronchial reactivity as measured by plethysmography in a

small group of individuals inoculated with a wild-type

influenza virus which persisted for at least 4 weeks. Such a

response was not seen in the volunteers inoculated with an

attenuated influenza virus. Laitinen et al. [1991] reported that

inoculation of volunteers with a live attenuated influenza

Cardiovascular conditionsCongestive heart failure 91% NR 23 adults with impaired left ventricular function Cabanes et al. [1989]Congestive heart failure 67% 16 12 adults with chronic left heart failure Pison et al. [1989]Mitral stenosis 53% 8 30 adults with mitral stenosis and no history of recent smoking, asthma,

or respiratory infectionsGulec et al. [1999]

C-reactive protein 42% 25 86 adults in highest tertile of sample for c-reactive protein levels Kony et al. [2004]Gastrointestinal conditions

Reflux 37% 8 30 adults with reflux and no history of asthma, allergies, and hadnever smoked

Bagnato et al. [2000]

Irritable bowel syndrome 73% 25 11adults with irritable bowel syndrome White et al. [1991]Inflammatory bowel disease 45% 16 38 adults with Crohn’s or ulcerative colitis Louis et al. [1995]Inflammatory bowel disease 19% 16 18 adults with Crohn’s disease Louis et al. [1999]Inflammatory bowel disease 27% NR 15 adults with Crohn’s disease Bartholo et al. [2005]

Autoimmune conditionsRheumatoid arthritis 55% 32 100 adults with rheumatoid arthritis Hassan et al. [1994]Rheumatoid arthritis 23% NR 18 newly diagnosed adults with rheumatoid arthritis Doyle et al. [2000]Sarcoidosis 50% 25 20 adults with sarcoidosis Bechtel et al. [1981]Sarcoidosis 45% 16 20 adults with newly diagnosed sarcoidosis and no history of current

smoking,COPD, allergic rhinitis, or recent upper respiratory tract infectionAggarwal et al. [2004]

AthletesFootball players 50% 25 151college football players Weiler et al. [1986]Hockey players 35% NR 26 Swiss hockey players, prevalence in Swiss population reported as16.4% Leuppi et al. [1998]Hockey players 24% NR 88 elite hockey players, histamine challenge, prevalence in 42 controls

was11%Lumme et al. [2003]

Various athletes 49% 16 100 elite athletes with no history of asthma, rhinitis, or recent respiratorillness; BHR in swimmers was 76%

Langdeau et al. [2000]

Endurance athletes 38% NR 39 endurance athletes (cross country skiers, triathletes) with no historyof allergic asthma, all nonsmokers

Verges et al. [2005]

MiscellaneousCoal mining 41% 100 22 non-smoking adult coal miners Hudgel and Roe [1988]Chronic lymphocytic leukemia 37% NR 19 adults with chronic lymphocytic leukemia Rolla et al. [1993]Gas cooking 21% 12.5 1,664 adults who use gas cooking appliances prevalence in those

using electric cooking was14%Kerkhof et al. [1999]

HIV infection 26% 12.5 248 men age 20^44 with HIV Poirier et al. [2001]Inhalant drug abuse 44% 25 91adults with a history of inhaling heroin mixed with cocaine Boto de los Bueis et al.

[2002]

BHR, bronchial hyperreactivity.NR, PC20 not reported, atypical protocol.aBHR criteriaAcited methacholine concentration (mg/ml) causing a 20% decrease in FEV1 (i.e., PC20). In those cases where a provocative dose (PD) was reported, the PC20 wasinterpreted as the maximum methacholine concentration corresponding to the PD.

TABLE III. (Continued )

Condition BHR rate BHR criteriaa Study population References


virus increased reactivity to histamine as measured by

plethysmography, despite an absence of clinical symptoms of

infection. The response appeared maximal on the second day

after inoculation and had disappeared by the ninth day.

The authors concluded that asymptomatic viral infections

can augment airway responsiveness in otherwise healthy

subjects.

Multiple studies have been performed regarding the

possibility of increased airway reactivity following influenza

vaccinations, in part based on anecdotal reports from

asthmatic patients who reported exacerbation of symptoms

after vaccination. Ouellette and Reed [1965] initially noted a

significant increase in response to methacholine among

individuals with asthma but not in individuals without

asthma after vaccination. de Jongste et al. [1984] noted that

asthmatic children showed increased airway responses to

histamine after administration of a live attenuated influenza

vaccine but showed no increased reactivity after use of an

inactivated influenza vaccine. More recent studies have

generally not shown a significant effect on BHR, even in

asthmatics, from influenza vaccinations [Reid et al., 1998;

Sener et al., 1999; Thomas et al., 1999].

Sinusitis generally has been associated with increased

rates of BHR, however there are relatively few studies

specifically examining this factor. This discrepancy may be

due in part to the fact that individuals with sinusitis frequently

have underlying allergic conditions such as allergic rhinitis

which makes it difficult to eliminate possible confounders.

Those studies which have examined this issue have reported a

high prevalence of BHR as might be expected [Bucca et al.,

1995; Okayama et al., 1998]. Additional evidence regarding

the effect of sinusitis on BHR is shown by decreases in BHR

responsiveness following sinusitis treatment [Bucca et al.,

1995; Oliveira et al., 1997; Tsao et al., 2003].

Mycoplasma pneumonia has been associated with a high

percentage of community acquired pneumonias. Symptoms

often persist for weeks to months with a dry hacking cough

and corresponding increases in BHR in a majority of patients.

Wongtim and Mogmued [1995] performed methacholine

challenges in 12 adults at 4 and 12 weeks after infection with

mycoplasma pneumonia. The participants were noted to be

previously healthy without any allergic diseases, asthma,

allergic rhinitis, and were nonsmokers. At the initial test,

67% were identified with BHR. A total of 50% were still

positive at 12 weeks after recovery indicating the persistence

of BHR after this type of infection.

Tobacco smoking

Smoking has been associated with increased BHR

in several studies and must be considered as a significant

confounder in interpreting methacholine challenge testing.

Casale et al. [1987, 1988] noted the prevalence of BHR in a

group of younger smokers was 35% compared to 28% in non-

smokers. Sparrow et al. [1987] reported BHR rates in a group

of over 400 males was 23.0% for never smokers, 26.7% for

ex-smokers, and 58.5% for current smokers.

Studies from the ECRHS using larger sample sizes have

confirmed the detrimental effects of smoking on BHR and

shown that BHR increases with continued smoking. Sunyer

et al. [1997] examined BHR in over 1100 non-atopic

participants from the ECRHS. The frequency of positive

methacholine challenges in women was 12.8%, 14.3%, and

23.6% for never, past, and current smokers, respectively. For

men, a similar relationship was seen with rates of 4.7%,

8.3%, and 17.9% for never, past, and current smokers. Chinn

et al. [2005] repeated methacholine challenge testing 10 years

later in a group of almost 4,000 participants in the ECRHS

who had an initial positive challenge. Those who continued

to smoke or restarted smoking during the interim showed

increased response to methacholine at follow-up. Non-

smokers showed no change in responsiveness. Other ECRHS

studies have shown smoking to be a significant risk factor for

BHR with odds ratios in excess of 2.0 [Petays et al., 2003].

Methacholine responsiveness may also increase significantly

with the number of cigarettes smoked per day [Schwartz

et al., 2002].

Exposure to passive cigarette smoke also has been

identified as a significant risk factor for BHR based on

analysis of ECRHS data [Janson et al., 2001]. The authors

noted the relationship between passive cigarette smoke

and BHR had not previously been assessed in the general

population. In a smaller study, Menon et al. [1992] examined

BHR to methacholine among 31 asthmatics and 39 non-

asthmatics who reported smoke sensitivity. After a 4-hr

controlled exposure to cigarette smoke in a test chamber, the

authors noted 32% of the asthmatics showed increased BHR

6 hr after the exposure. In 16%, increased BHR was evident

one week after the exposure. Of those without asthma, 18%

showed increased BHR 6 hr after the exposure. In 2 subjects,

one with asthma and one without, increased BHR was noted

to persist for up to 8 weeks afterwards.

Chronic respiratory conditions

Increased rates for BHR, sometimes in excess of 50%

have been reported in testing of individuals with chronic

bronchitis [Ramsdell et al., 1982; Ramsdale et al., 1984;

Bahous et al., 1984a; Okayama et al., 1998]; chronic

obstructive pulmonary disease [Yan et al., 1985; Greenspon

and Parrish, 1988]; and bronchiectasis [Bahous et al., 1984b;

Pang et al., 1989; Ip et al., 1991].

Cardiovascular disease

Several heart conditions have been identified as risk

factors for BHR such as mitral valve stenosis [Rolla

776 Hewitt

et al., 1990; Gulec et al., 1999] and congestive heart failure

[Cabanes et al., 1989; Pison et al., 1989]. Possible expla-

nations for BHR in this subset of individuals include

interstitial lung edema, vascular reactivity of the bronchial

wall, and decreased airway caliber. Saitoh et al. [1994] noted

that individuals with vasospastic angina had an increased

response to acetylcholine compared to individuals with

chest pain syndrome and suggested that individuals with

coronary vasospasm may have systemic smooth muscle

hypercontractility.

C-reactive protein (CRP), which has been associated

with an increased risk of adverse cardiovascular events has

also been associated with increased BHR [Kony et al., 2004].

It was suggested that CRP may be a marker of systemic

inflammation affecting the respiratory tract. BHR has also

been associated with common carotid intima-media thick-

ness in men [Zureik et al., 2004].

Gastrointestinal disorders

Multiple studies have identified gastrointestinal disor-

ders such as irritable bowel syndrome (IBS), Crohn’s disease,

ulcerative colitis, and gastroesophageal reflux (GERD) as

risk factors for BHR [White et al., 1991; Louis et al., 1995,

1999; Bartholo et al., 2005]. In the case of IBS, White et al.

[1991] suggested these individuals may have common

alterations in smooth muscle function outside the gastro-

intestinal tract.

Gastroesophageal reflux (GERD) has been associated

with both asthma [Stein, 2003] and BHR. Bagnato et al.

[2000] reported the prevalence of BHR in individuals with

GERD was 37% compared to 7% in a control group. Both

groups were noted to have no history of asthma, no significant

airborne allergies, and had never smoked. The authors noted

that GERD may predispose to asthma due to microaspiration

of gastric contents into the lung. Kiljander et al. [2002] noted

that the degree of bronchial reactivity in patients with GERD

correlated with the severity of distal esophageal reflux. Also,

bronchial reactivity significantly decreased in 3 asthmatic

patients who underwent surgical fundoplication to control

their reflux. Vincent et al. [1997] reported a significant

association in asthmatics between the degree of BHR and

number of reflux episodes per day.

Autoimmune diseases

A number of autoimmune diseases such as rheumatoid

arthritis, Sjogren’s syndrome, and sarcoidosis have been

identified as having an increased prevalence of respiratory

abnormalities including obstructive lung disease and BHR

[Geddes et al., 1979; Bechtel et al., 1981; Gudbjornsson et al.,

1991; Hassan et al., 1994; Doyle et al., 2000; Aggarwal et al.,

2004]. For example, Doyle et al. [2000] noted that as many as

60% of rheumatoid arthritis patients may demonstrate

respiratory abnormalities such as obstructive lung disease.

In a series of 100 rheumatoid patients, Hassan et al. [1994]

reported 55% had BHR compared to 16% of controls. BHR in

these patients is possibly secondary to associated inflamma-

tory effects within the respiratory tract.

Elite athletes

Studies have consistently found increased BHR rates in

athletes from a number of different sports such as ice hockey

[Leuppi et al., 1998; Lumme et al., 2003]; cross-country

skiers [Larsson et al., 1993; Verges et al., 2005]; swimming

[Langdeau et al., 2000]; and football players [Weiler et al.,

1986]. Many of the studies have been associated with cold

weather sports. It was suggested that strenuous exercise at

low temperatures entailed breathing of large volumes of

cold air which contribute to the reactivity. In swimmers

the proposed mechanisms for BHR were related to the

composition of inspired air and inflammation. Helenius et al.

[2002] noted that BHR decreased or disappeared in some

swimmers who stopped high-level training.

Miscellaneous

Numerous other population groups or health conditions

have been linked to BHR which provides further evidence of

the poor specificity of the test. These include pig farming

[Vogelzang et al., 1997], coal mining [Hudgel and Roe,

1988], firefighting [Sherman et al., 1989], obesity [Chinn

et al., 2002; Litonjua et al., 2002], chronic lymphocytic

leukemia [Rolla et al., 1993], vocal cord dysfunction [Perkins

and Morris, 2002], gas cooking [Kerkhof et al., 1999],

inhalational drug abuse [Tashkin et al., 1993; Boto de los

Bueis et al., 2002], endotoxins [Malmberg and Larsson,

1993], traumatic spinal cord injury [Dicpinigaitis et al., 1994],

antishock trousers [Regnard et al., 1990], dietary factors

[Soutar et al., 1997], mastocytosis [Mochizuki et al., 2002],

human immunodeficiency virus infection [Poirier et al., 2001],

tuberculosis [Park et al., 1989], Chlamydia pneumoniae

and Chlamydia trachomatis [Bjornsson et al., 1996]; family

history [Koh et al., 1998], and a history of severe perinatal

respiratory infections [Vonk et al., 2004]. A common

pathophysiological mechanism for BHR in this diverse group

is not readily apparent, although many of the conditions may

be associated with varying degrees of airway inflammation.

CONCLUSION

Methacholine challenge testing can be used for the

diagnosis of asthma and RADS and also provide an index of

the severity of airway reactivity. However, due to multiple

factors including test methodology, interpretive criteria,

background rates of BHR within the general population, and

numerous conditions which have been associated with BHR,


results must be interpreted cautiously. It is difficult to predict

on an individual basis the relative significance of many of

the variables that can affect methacholine challenge test

interpretation. A negative methacholine challenge generally

provides strong evidence that an individual does not have

asthma or an asthma-like condition as nearly all individuals

with significant asthma will react to methacholine at low

doses. However, a positive methacholine challenge does not

necessarily confirm an individual has asthma or even a

clinically significant respiratory condition. For the occupa-

tional medicine physician evaluating respiratory claims

secondary to inhalation exposures, the possibility of pre-

existing BHR due to the above reviewed factors must be

considered and adequately excluded before concluding a

causal association exists between the exposure and a positive

methacholine challenge.

REFERENCES

Aggarwal AN, Gupta D, Chandrasekhar G, Jindal SK. 2004. Bronchialhyperresponsiveness in patients with sarcoidosis. J Assoc PhysiciansIndia 52:21–23.

Bagnato GF, Gulli S, Giacobbe O, De Pasquale R, Purello D’AmbrosioF. 2000. Bronchial hyperresponsiveness in subjects with gastro-esophageal reflux. Respiration 67(5):507–509.

Bahous J, Cartier A, Ouimet G, Pineau L, Malo JL. 1984a. Nonallergicbronchial hyperexcitability in chronic bronchitis. Am Rev Respir Dis129(2):216–220.

Bahous J, Cartier A, Pineau L, Bernard C, Ghezzo H, Martin RR,Malo JL. 1984b. Pulmonary function tests and airway responsiveness tomethacholine in chronic bronchiectasis of the adult. Bull EurPhysiopathol Respir 20(4):375–380.

Bartholo RM, Zaltman C, Elia C, Cardoso AP, Flores V, Lago P,Cassabian L, Dorileo FC, Lapa-e-Silva JR. 2005. Bronchial hyper-responsiveness and analysis of induced sputum cells in Crohn’s disease.Braz J Med Biol Res 38(2):197–203.

Bechtel JJ, Starr T III, Dantzker DR, Bower JS. 1981. Airwayhyperreactivity in patients with sarcoidosis. Am Rev Respir Dis124(6):759–761.

Beckett WS, Pace PA, Sferlaaza SJ, Carey VJ, Weiss ST. 1997. Annualvariability in methacholine responsiveness in nonasthmatic workingadults. Eur Respir J 10(11):2515–2521.

Bjornsson E, Hjelm E, Janson C, Fridell E, Boman G. 1996. Serology ofchlamydia in relation to asthma and bronchial hyperresponsiveness.Scand J Infect Dis 28(1):63–69.

Boto de los Bueis A, Pereira Vega A, Sanchez Ramos JL, MaldonadoPerez JA, Ayerbe Garcia R, Garcia Jimenez D, Pujol de la Llave E. 2002.Bronchial hyperreactivity in patients who inhale heroin mixed withcocaine vaporized on aluminum foil. Chest 121(4):1223–1230.

Bourbeau J, Delfino R, Ernst P. 1993. Tracheal size is a determinant ofthe bronchoconstrictive response to inhaled methacholine. Eur Respir J6(7):991–995.

Brooks SM, Weiss MA, Bernstein IL. 1985. Reactive airwaysdysfunction syndrome (RADS). Persistent asthma syndrome after highlevel irritant exposures. Chest 88(3):376–384.

Brown RH, Croisille P, Mudge B, Diemer FB, Permutt S, Togias A.2000. Airway narrowing in healthy humans inhaling methacholine

without deep inspirations demonstrated by HRCT. Am J Respir CritCare Med 161(4 Pt 1):1256–1263.

Bucca C, Rolla G, Scappaticci E, Chiampo F, Bugiani M, Mangnano M,D’Alberto M. 1995. Extrathoracic and intrathoracic airway responsive-ness in sinusitis. J Allergy Clin Immunol 95:52–59.

Cabanes LR, Weber SN, Matran R, Regnard J, Richard MO, DegeorgesME, Lockhart A. 1989. Bronchial hyperresponsiveness to methacholinein patients with impaired left ventricular function. N Engl J Med320(20):1317–1322.

Casale TB, Rhodes BJ, Donnelly AL, Weiler JM. 1987. Airwayresponses to methacholine in asymptomatic nonatopic cigarettesmokers. J Appl Physiol 62(5):1888–1892.

Casale TB, Rhodes BJ, Donnelly AL, Weiler JM. 1988. Airwayreactivity to methacholine in nonatopic asymptomatic adults. J ApplPhysiol 64(6):2558–2561.

Chinn S, Burney P, Jarvis D, Luczynska C. 1997. Variation in bronchialresponsiveness in the European Community Respiratory Health Survey(ECRHS). Eur Respir J 10(11):2495–2501.

Chinn S, Burney P, Sunyer J, Jarvis D, Luczynska C. 1999. Sensitizationto individual allergens and bronchial responsiveness in the ECRHS.European Community Respiratory Health Survey. Eur Respir J 14(4):876–884.

Chinn S, Jarvis D, Burney P. 2002. Relation of bronchial responsivenessto body mass index in the ECRHS. European Community RespiratoryHealth Survey. Thorax 57(12):1028–1033.

Chinn S, Jarvis D, Luczynska CM, Ackermann-Liebrich U, Anto JM,Cerveri I, de Marco R, Gislason T, Heinrich J, Janson C, Kunzli N,Leynaert B, Neukirch F, Schouten JP, Sunyer J, Svanes C, Wjst M,Burney PG. 2005. An increase in bronchial responsiveness is associatedwith continuing or restarting smoking. Am J Respir Crit Care Med172(8):956–961.

Chowgule RV, Shetye VM, Parmar JR, Bhosale AM, Khandagale MR,Phalnitkar SV, Gupta PC. 1998. Prevalence of respiratory symptoms,bronchial hyperreactivity, and asthma in a megacity. Results of theEuropean community respiratory health survey in Mumbai (Bombay).Am J Respir Crit Care Med 158(2):547–554.

Ciprandi G, Cirillo I, Tosca MA, Vizzaccaro A. 2004a. Bronchialhyperreactivity and spirometric impairment in patients with perennialallergic rhinitis. Int Arch Allergy Immunol 133(1):14–18.

Ciprandi G, Cirillo I, Tosca MA, Vizzaccaro A. 2004b. Bronchialhyperreactivity and spirometric impairment in patients with seasonalallergic rhinitis. Respir Med 98(9):826–831.

Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG,MacIntyre NR, McKay RT, Wanger JS, Anderson SD, Cockcroft DW,Fish JE, Sterk PJ. 2000. Guidelines for methacholine and exercisechallenge testing-1999. This official statement of the AmericanThoracic Society was adopted by the ATS Board of Directors, July1999. Am J Respir Crit Care Med 161(1):309–329.

de Jongste JC, Degenhart HJ, Neijens HJ, Duiverman EJ, Raatgeep HC,Kerrebijn KF. 1984. Bronchial responsiveness and leucocyte reactivityafter influenza vaccine in asthmatic patients. Eur J Respir Dis65(3):196–200.

Di Lorenzo G, Pacor ML, Mansueto P, Esposito Pellitteri M, Lo BiancoC, Ditta V, Leto-Barone MS, Napoli N, Di Fede G, Rini GB. 2005.Determinants of bronchial hyperresponsiveness in subjects with rhinitis.Int J Immunopathol Pharmacol 18(4):715–722.

Dicpinigaitis PV, Spungen AM, Bauman WA, Absgarten A, AlmenoffPL. 1994. Bronchial hyperresponsiveness after cervical spinal cordinjury. Chest 105(4):1073–1076.

Doyle JJ, Eliasson AH, Argyros GJ, Dennis GJ, Finger DR, HurwitzKM, Phillips YY. 2000. Prevalence of pulmonary disorders in patients

778 Hewitt

with newly diagnosed rheumatoid arthritis. Clin Rheumatol 19(3):217–221.

Drezen JM. 2008. Asthma. Chapter 87. In: Goldman L, Ausiello D,editors. Cecil medicine. 23rd edition. Philadelphia: W.B. Saunders.pp 612–619.

Dreborg S. 1996. Impact of allergen exposure on bronchial hyper-responsiveness. Pediatr Allergy Immunol 7 (9 Suppl):14–17.

Drotar DE, Davis BE, Cockcroft DW. 1999. Dose versus concentrationof methacholine. Ann Allergy Asthma Immunol 83(3):229–230.

Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadel JA. 1976.Mechanisms of bronchial hyperreactivity in normal subjects after upperrespiratory tract infection. Am Rev Respir Dis 113(2):131–139.

Enarson DA, Schulzer M, Vedal S, Chan-Yeung M. 1987. Summarizingmethacholine bronchoprovocation data in epidemiological surveys.Bull Eur Physiopathol Respir 23(4):387–389.

Ernst P, Ghezzo H, Becklake MR. 2002. Risk factors for bronchialhyperresponsiveness in late childhood and early adolescence. EurRespir J 20(3):635–639.

Geddes DM, Webley M, Emerson PA. 1979. Airways obstruction inrheumatoid arthritis. Ann Rheum Dis 38(3):222–225.

Greenspon LW, Parrish B. 1988. Inhibition of methacholine-inducedbronchoconstriction in patients with chronic obstructive pulmonarydisease. Am Rev Respir Dis 137(2):281–285.

Gudbjornsson B, Hedenstrom H, Stalenheim G, Hallgren R. 1991.Bronchial hyperresponsiveness to methacholine in patients withprimary Sjogren’s syndrome. Ann Rheum Dis 50(1):36–40.

Gulec S, Ertas F, Tutar E, Demirel Y, Karaoguz R, Omurlu K, Oral D.1999. Bronchial hyperreactivity in patients with mitral stenosis beforeand after successful percutaneous mitral balloon valvulotomy. Chest116(6):1582–1586.

Hargreave FE, Ryan G, Thomson NC, O’Byrne PM, Latimer K, JuniperEF, Dolovich J. 1981. Bronchial responsiveness to histamine ormethacholine in asthma: Measurement and clinical significance.J Allergy Clin Immunol 68(5):347–355.

Hassan WU, Keaney NP, Holland CD, Kelly CA. 1994. Bronchialreactivity and airflow obstruction in rheumatoid arthritis. Ann RheumDis 53(8):511–514.

Helenius I, Rytila P, Sarna S, Lumme A, Helenius M, Remes V, HaahtelaT. 2002. Effect of continuing or finishing high-level sports on airwayinflammation, bronchial hyperresponsiveness, and asthma: A 5-yearprospective follow-up study of 42 highly trained swimmers. J AllergyClin Immunol 109(6):962–968.

Hobbins TE, Hughes TP, Rennels MB, Murphy BR, Levine MM. 1982.Bronchial reactivity in experimental infections with influenza virus.J Infect Dis 146(4):468–471.

Hudgel DW, Roe R. 1988. Nonspecific airway hyperreactivity innonsmoking bituminous coal miners demonstrated by quantitativemethacholine inhalation challenge. J Lab Clin Med 111(6):684–691.

Ip M, Lam WK, So SY, Liong E, Chan CY, Tse KM. 1991. Analysis offactors associated with bronchial hyperreactivity to methacholine inbronchiectasis. Lung 169(1):43–51.

Jang AS. 2002. Nasal eosinophilic inflammation contributes tobronchial hyperresponsiveness in patients with allergic rhinitis.J Korean Med Sci 17(6):761–764.

Janson C, Chinn S, Jarvis D, Zock JP, Toren K, Burney P. 2001. Effect ofpassive smoking on respiratory symptoms, bronchial responsiveness,lung function, and total serum IgE in the European CommunityRespiratory Health Survey: A cross-sectional study. Lancet 358(9299):2103–2109.

Jayet PY, Schindler C, Kunzli N, Zellweger JP, Brandli O, PerruchoudAP, Keller R, Schwartz J, Ackermann-Liebrich U, Leuenberger P. 2005.Reference values for methacholine reactivity (SAPALDIA study).Respir Res 6:131.

Kerkhof M, de Monchy JG, Rijken B, Schouten JP. 1999. The effect ofgas cooking on bronchial hyperresponsiveness and the role ofimmunoglobulin E. Eur Respir J 14(4):839–844.

Kerkhof M, Postma DS, Schouten JP, de Monchy JG. 2003. Allergicsensitization to indoor and outdoor allergens and relevance to bronchialhyperresponsiveness in younger and older subjects. Allergy 58(12):1261–1267.

Kiljander TO, Salomaa ER, Hietanen EK, Ovaska J, Helenius H, LiippoK. 2002. Gastroesophageal reflux and bronchial responsiveness: Corre-lation and the effect of fundoplication. Respiration 69(5):434–439.

Kleerup E, Tashkin DP. 1997. Relative effects of concentration andcumulative dose of inhaled methacholine of bronchial responses (BR) inasthmatic subjects. Am Rev Resp Dis 147 (Suppl):A257.

Koh YY, Lee MH, Kim CK, Min YG, Kim YK, Min KU, Kim YY. 1998.A familial predisposition in bronchial hyperresponsiveness amongpatients with allergic rhinitis. J Allergy Clin Immunol 102 (6 Pt 1):921–926.

Kongerud J, Soyseth V, Johansen B. 1989. Room temperature influencesoutput from the Wright jet nebulizer. Eur Respir J 2(7):681–684.

Kony S, Zureik M, Driss F, Neukirch C, Leynaert B, Neukirch F. 2004.Association of bronchial hyperresponsiveness and lung function withC-reactive protein (CRP): A population based study. Thorax 59(10):892–896.

Laitinen LA, Elkin RB, Empey DW, Jacobs L, Mills J, Nadel JA. 1991.Bronchial hyperresponsiveness in normal subjects during attenuatedinfluenza virus infection. Am Rev Respir Dis 143(2):358–361.

Langdeau JB, Turcotte H, Bowie DM, Jobin J, Desgagne P, Boulet LP.2000. Airway hyperresponsiveness in elite athletes. Am J Respir CritCare Med 161(5):1479–1484.

Larsson K, Ohlsen P, Larsson L, Malmberg P, Rydstrom PO, Ulriksen H.1993. High prevalence of asthma in cross country skiers. Br Med J307(6915):1326–1329.

Leone C, Teodoro C, Pelucchi A, Mastropasqua B, Cavigioli G,Marazzini L, Foresi A. 1997. Bronchial responsiveness and airwayinflammation in patients with nonallergic rhinitis with eosinophiliasyndrome. J Allergy Clin Immunol 100(6 Pt 1):775–780.

Leuppi JD, Kuhn M, Comminot C, Reinhart WH. 1998. High prevalenceof bronchial hyperresponsiveness and asthma in ice hockey players. EurRespir J 12(1):13–16.

Leynaert B, Bousquet J, Henry C, Liard R, Neukirch F. 1997. Isbronchial hyperresponsiveness more frequent in women than in men? Apopulation-based study. Am J Respir Crit Care Med 156(5):1413–1420.

Litmanovitch M, Kivity S, Soferman R, Topilsky M. 1990. Relationshipbetween recurrent croup and airway hyperreactivity. Ann Allergy65(3):239–241.

Litonjua AA, Sparrow D, Celedon JC, DeMolles D, Weiss ST. 2002.Association of body mass index with the development of methacholineairway hyperresponsiveness in men: The Normative Aging Study.Thorax 57(7):581–585.

Louis E, Louis R, Drion V, Bonnet V, Lamproye A, Radermecker M,Belaiche J. 1995. Increased frequency of bronchial hyperresponsivenessin patients with inflammatory bowel disease. Allergy 50(9):729–733.

Louis E, Louis R, Shute J, Lau L, Franchimont D, Lamproye A,Radermecker M, Djukanovic R, Belaiche J. 1999. Bronchial eosino-philic infiltration in Crohn’s disease in the absence of pulmonarydisease. Clin Exp Allergy 29(5):660–666.


Lumme A, Haahtela T, Ounap J, Rytila P, Obase Y, Helenius M, RemesV, Helenius I. 2003. Airway inflammation, bronchial hyperresponsive-ness and asthma in elite ice hockey players. Eur Respir J 22(1):113–117.

Malmberg P, Larsson K. 1993. Acute exposure to swine dust causesbronchial hyperresponsiveness in healthy subjects. Eur Respir J 6(3):400–404.

Malo JL, Pineau L, Cartier A, Martin RR. 1983. Reference values of theprovocative concentrations of methacholine that cause 6% and 20%changes in forced expiratory volume in one second in a normalpopulation. Am Rev Respir Dis 128(1):8–11.

Menon P, Rando RJ, Stankus RP, Salvaggio JE, Lehrer SB. 1992. Passivecigarette smoke-challenge studies: Increase in bronchial hyperreactiv-ity. J Allergy Clin Immunol 89(2):560–566.

Mochizuki H, Morikawa A, Kurosawa M. 2002. Bronchial hyper-responsiveness in a patient with systemic mastocytosis. Respirology7(3):285–288.

Mosby’s Drug Consult. 2007. Methacholine chloride. Mosby’s DrugConsult. CD-ROM 2007. St. Louis: Mosby Elsevier.

Okayama M, Iijima H, Shimura S, Shimomura A, Ikeda K, Okayama H,Shirato K. 1998. Methacholine bronchial hyperresponsiveness inchronic sinusitis. Respiration 65(6):450–457.

Oliveira CA, Sole D, Naspitz CK, Rachelefsky GS. 1997. Improve-ment of bronchial hyperresponsiveness in asthmatic children treatedfor concomitant sinusitis. Ann Allergy Asthma Immunol 79(1):70–74.

Ouellette JJ, Reed CE. 1965. Increased response of asthmatic subjects tomethacholine after influenza vaccine. J Allergy 36(6):558–563.

Pang J, Chan HS, Sung JY. 1989. Prevalence of asthma, atopy, andbronchial hyperreactivity in bronchiectasis: A controlled study. Thorax44(11):948–951.

Park IW, Kim SH, Chang EH, Choi BW, Hue SH, Seo SC. 1989. A studyof the bronchial provocation test with methacholine in patients withactive pulmonary tuberculosis. Korean J Intern Med 4(1):59–64.

Perkins PJ, Morris MJ. 2002. Vocal cord dysfunction induced bymethacholine challenge testing. Chest 122(6):1988–1993.

Petays T, von Hertzen L, Metso T, Rytila P, Jousilahti P, Helenius I,Vartiainen E, Haahtela T. 2003. Smoking and atopy as determinants ofsputum eosinophilia and bronchial hyper-responsiveness in adults withnormal lung function. Respir Med 97(8):947–954.

Pison C, Malo JL, Rouleau JL, Chalaoui J, Ghezzo H, Malo J. 1989.Bronchial hyperresponsiveness to inhaled methacholine in subjects withchronic left heart failure at a time of exacerbation and after increasingdiuretic therapy. Chest 96(2):230–235.

Poirier CD, Inhaber N, Lalonde RG, Ernst P. 2001. Prevalence ofbronchial hyperresponsiveness among HIV-infected men. Am J RespirCrit Care Med 164(4):542–545.

Prieto L, Marin J. 1990. Measurement of response to methacholineinhalation challenge in asthma and allergic rhinitis. PC20 orPC35FEV1? Allergol Immunopathol 18:285–289.

Prieto L, Berto JM, Gutierrez V. 1994. Airway responsiveness tomethacholine and risk of asthma in patients with allergic rhinitis. AnnAllergy 72(6):534–539.

Ramsdale EH, Morris MM, Roberts RS, Hargreave FE. 1984. Bronchialresponsiveness to methacholine in chronic bronchitis: Relationship toairflow obstruction and cold air responsiveness. Thorax 39(12):912–918.

Ramsdale EH, Morris MM, Roberts RS, Hargreave FE. 1985.Asymptomatic bronchial hyperresponsiveness in rhinitis. J AllergyClin Immunol 75(5):573–577.

Ramsdell JW, Nachtwey FJ, Moser KM. 1982. Bronchial hyper-reactivity in chronic obstructive bronchitis. Am Rev Respir Dis126(5):829–832.

Regnard J, Baudrillard P, Salah B, Dinh Xuan AT, Cabanes L, LockhartA. 1990. Inflation of antishock trousers increases bronchial response tomethacholine in healthy subjects. J Appl Physiol 68(3):1528–1533.

Reid DW, Bromly CL, Stenton SC, Hendrick DJ, Bourke SJ. 1998. Adouble-blind placebo-controlled study of the effect of influenzavaccination on airway responsiveness in asthma. Respir Med 92(8):1010–1011.

Rijcken B, Schouten JP, Weiss ST, Speizer FE, van der Lende R. 1987.The relationship of nonspecific bronchial responsiveness to respiratorysymptoms in a random population sample. Am Rev Respir Dis 136(1):62–68.

Rolla G, Bucca C, Caria E, Scappaticci E, Baldi S. 1990. Bronchialresponsiveness in patients with mitral valve disease. Eur Respir J3(2):127–131.

Rolla G, Bucca C, Chiampo F, Brussino L, Scappaticci E, Stacchini A,Bertero MT, Caligaris-Cappio F. 1993. Respiratory symptoms, lungfunction tests, airway responsiveness, and bronchoalveolar lymphocytesubsets in B-chronic lymphocytic leukemia. Lung 171(5):265–275.

Roth BJ, Hammers LM, Dillard TA. 2001. Methacholine challengetesting in Reserve Officer Training Corps cadets. Chest 119(3):701–707.

Saitoh Y, Sasaki F, Ishizaki T, Miyabo S, Kanamori K, Mifune J. 1994.Bronchial hyperresponsiveness to acetylcholine in patients with vaso-spastic angina pectoris. Chest 105(2):364–367.

Schwartz J, Schindler C, Zemp E, Perruchoud AP, Zellweger JP,Wuthrich B, Leuenberger P, Ackermann-Liebrich U. 2002. Predictors ofmethacholine responsiveness in a general population. Chest 122(3):812–820.

Sener M, Gursel G, Turktas H. 1999. Effects of inactivated influenzavirus vaccination on bronchial reactivity symptom scores and peakexpiratory flow variability in patients with asthma. JAsthma 36(2):165–169.

Sherman CB, Barnhart S, Miller MF, Segal MR, Aitken M, Shoene R,Daniell W, Rosenstock L. 1989. Firefighting acutely increases airwayresponsiveness. Am Rev Respir Dis 140(1):185–190.

Soutar A, Seaton A, Brown K. 1997. Bronchial reactivity and dietaryantioxidants. Thorax 52(2):166–170.

Sparrow D, O’Connor G, Colton T, Barry CL, Weiss ST. 1987. Therelationship of nonspecific bronchial responsiveness to the occurrenceof respiratory symptoms and decreased levels of pulmonary function.The Normative Aging Study. Am Rev Respir Dis 135(6):1255–1260.

Spector S, Luparello TJ, Kopetzky MT, Souhrada J, Kinsman RA. 1976.Response of asthmatics to methacholine and suggestion. Am Rev RespirDis 113(1):43–50.

Stein MR. 2003. Possible mechanisms of influence of esophageal acidon airway hyperresponsiveness. Am J Med 115 (Suppl 3A):55S–59S.

Sunyer J, Anto JM, Kogevinas M, Soriano JB, Tobias A, Munoz A.1997. Smoking and bronchial responsiveness in nonatopic and atopicyoung adults. Spanish Group of the European Study of Asthma. Thorax52(3):235–238.

Tashkin DP, Simmons MS, Chang P, Liu H, Coulson AH. 1993. Effectsof smoked substance abuse on nonspecific airway hyperresponsiveness.Am Rev Respir Dis 147(1):97–103.

Thaminy A, Lamblin C, Perez T, Bergoin C, Tonnel AB, Wallaert B.2000. Increased frequency of asymptomatic bronchial hyperresponsive-ness in nonasthmatic patients with food allergy. Eur Respir J16(6):1091–1094.

780 Hewitt

Thomas PS, Ng C, Elsing M, Yates DH. 1999. Influenza vaccination:Changes in exhaled nitric oxide levels and sputum cytology.Respirology 4(4):355–358.

Townley RG, Ryo UY, Kolotkin BM, Kang B. 1975. Bronchialsensitivity to methacholine in current and former asthmatic and allergicrhinitis patients and control subjects. J Allergy Clin Immunol56(6):429–442.

Trigg CJ, Bennett JB, Tooley M, Sibbald B, D’Souza MF, Davies RJ.1990. A general practice based survey of bronchial hyperresponsivenessand its relation to symptoms, sex, age, atopy, and smoking. Thorax45(11):866–872.

Tsao CH, Chen LC, Yeh KW, Huang JL. 2003. Concomitant chronicsinusitis treatment in children with mild asthma: The effect on bronchialhyperresponsiveness. Chest 123(3):757–764.

Vandenplas O, Malo J-L. 1997. Inhalation challenges with agentscausing occupational asthma. Eur Respir J 10(10):2612–2629.

Verges S, Devouassoux G, Flore P, Rossini E, Fior-Gozlan M, Levy P,Wuyam B. 2005. Bronchial hyperresponsiveness, airway inflammation,and airflow limitation in endurance athletes. Chest 127(6):1935–1941.

Vincent D, Cohen-Jonathan AM, Leport J, Merrouche M, Geronimi A,Pradalier A, Soule JC. 1997. Gastro-oesophageal reflux prevalence andrelationship with bronchial reactivity in asthma. Eur Respir J10(10):2255–2259.

Vogelzang PF, van der Gulden JW, Preller L, Tielen MJ, van SchayckCP, Folgering H. 1997. Bronchial hyperresponsiveness and exposure inpig farmers. Int Arch Occup Environ Health 70(5):327–333.

Vonk JM, Boezen HM, Postma DS, Schouten JP, van Aalderen WM,Boersma ER. 2004. Perinatal risk factors for bronchial hyperrespon-siveness and atopy after a follow-up of 20 years. JAllergy Clin Immunol114(2):270–276.

Wallaert B, Gosset P, Lamblin C, Garcia G, Perez T, Tonnel AB. 2002.Airway neutrophil inflammation in nonasthmatic patients with foodallergy. Allergy 57(5):405–410.

Wassmer G, Jorres RA, Heinrich J, Wjst M, Reitmeir P, WichmannHE. 1997. The association between baseline lung function andbronchial responsiveness to methacholine. Eur J Med Res 2(2):47–54.

Weiler JM, Metzger WJ, Donnelly AL, Crowley ET, Sharath MD. 1986.Prevalence of bronchial hyperresponsiveness in highly trained athletes.Chest 90(1):23–28.

Wennergren G. 1996. Impact of viral infection on bronchial hyper-responsiveness. Pediatr Allergy Immunol 7(9 Suppl):10–13.

White AM, Stevens WH, Upton AR, O’Byrne PM, Collins SM. 1991.Airway responsiveness to inhaled methacholine in patients with irritablebowel syndrome. Gastroenterology 100(1):68–74.

Wong GW, Li ST, Hui DS, Fok TF, Zhong NS, Chen YZ, Lai CK.2002. Individual allergens as risk factors for asthma and bronchialhyperresponsiveness in Chinese children. Eur Respir J 19(2):288–293.

Wongtim S, Mogmued S. 1995. Methacholine inhalation challenge inpatients with post-Mycoplasma pneumoniae pneumonia. Asian Pac JAllergy Immunol 13(1):5–10.

Yan K, Salome M, Woolcock AJ. 1985. Prevalence and nature ofbronchial hyperresponsiveness in subjects with chronic obstructivepulmonary disease. Am Rev Respir Dis 132(1):25–29.

Zureik M, Kony S, Neukirch C, Courbon D, Leynaert B, Vervloet D,Ducimetiere P, Neukirch F. 2004. Bronchial hyperresponsiveness tomethacholine is associated with increased common carotid intima-media thickness in men. Arterioscler Thromb Vasc Biol 24(6):1098–1103.


interpretation of the “positive” methacholine challenge

Documents