Investigating Clinical Bronchiolitis Investigating Clinical Bronchiolitis Obliterans: Obliterans: clinicians + researchers = teamclinicians + researchers = team

Francine Lortie-Monette, MD, MSc, CSPQ, MBAFrancine Lortie-Monette, MD, MSc, CSPQ, MBA

Department of Epidemiology and BiostatisticsDepartment of Epidemiology and Biostatistics

University of Western OntarioUniversity of Western Ontario

20032003

ReferencesReferences

Kreiss K, Gomaa A, Kullman G, Fedan Kreiss K, Gomaa A, Kullman G, Fedan K et al. N Engl J Med 2002;347(5):330-8K et al. N Engl J Med 2002;347(5):330-8

Schacter EN, N Engl J Med 2002; Schacter EN, N Engl J Med 2002; 347(5):360-1347(5):360-1

NIOSH Fact Sheet July 2002NIOSH Fact Sheet July 2002

Index PatientIndex Patient

A housewife:A housewife: First job in October 1993, at the age of 40, First job in October 1993, at the age of 40,

on the microwave-popcorn packaging line on the microwave-popcorn packaging line at the plant.at the plant.

No chest symptomsNo chest symptoms Had never smokedHad never smoked Walked several hours/dayWalked several hours/day

First symptomsFirst symptoms

5 months later:5 months later: Starts coughing about three hours after the Starts coughing about three hours after the

start of her evening shift, start of her evening shift, without any changes in her work environment without any changes in her work environment

or her usual seated job activities and or her usual seated job activities and without any improvement when away from without any improvement when away from

work.work.

Later SymptomsLater Symptoms

Two to three weeks later:Two to three weeks later: Myalgias, night sweats, and exercise-induced Myalgias, night sweats, and exercise-induced

exacerbation of the cough.exacerbation of the cough. Evolving into:Evolving into:

Exertional dyspneaExertional dyspnea In April (6 months post DOH):In April (6 months post DOH):

Dry cough becomes productiveDry cough becomes productive Allergist diagnoses: bronchitis, hay fever, and Allergist diagnoses: bronchitis, hay fever, and

asthmaasthma Bronchodilator: no improvement in symptoms.Bronchodilator: no improvement in symptoms.

Observations – In June:Observations – In June:

FEVFEV11: 0.86 liter (30% of predicted): 0.86 liter (30% of predicted)

FVC: 2.27 liters (66% of predicted)FVC: 2.27 liters (66% of predicted)

Normal diffusing capacity for carbon Normal diffusing capacity for carbon monoxide.monoxide.

Stopped workStopped work

Stops working in mid-June Stops working in mid-June Having lost 8 lb (3.6 kg) over the course Having lost 8 lb (3.6 kg) over the course

of her employment. of her employment. Dyspnea increased, but cough slowly Dyspnea increased, but cough slowly

improved.improved.

Further testsFurther tests

In October 1994 (one yr post DOH):In October 1994 (one yr post DOH): Tests worseTests worse

Tomography:Tomography: Minimal, diffuse bronchial-wall thickening; air Minimal, diffuse bronchial-wall thickening; air

trapping; and right-upper-lobe granulomatrapping; and right-upper-lobe granuloma Thoracoscopic lung biopsy:Thoracoscopic lung biopsy:

Scattered, non-necrotizing granulomas; focal Scattered, non-necrotizing granulomas; focal bronchiolar fibrosis; fibroblast proliferation bronchiolar fibrosis; fibroblast proliferation compressing one bronchiolar lumencompressing one bronchiolar lumen

TreatmentsTreatments

No response to high-dose prednisone No response to high-dose prednisone Only a symptomatic response to a three-Only a symptomatic response to a three-

month course of cyclophosphamide month course of cyclophosphamide

Placed on a waiting list for a lung Placed on a waiting list for a lung transplant in November 1995 transplant in November 1995

FEVFEV1 1 in December 2001: 0.61 liter (21% in December 2001: 0.61 liter (21% of predicted)of predicted)

Identification of a cluster Identification of a cluster

The Missouri Department of Health learns that, by The Missouri Department of Health learns that, by May 2000, eight persons who had formerly worked at May 2000, eight persons who had formerly worked at a microwave popcorn plant had been diagnosed with a microwave popcorn plant had been diagnosed with bronchiolitis obliterans.bronchiolitis obliterans.

No incident of overexposure No incident of overexposure

Four had worked in the room where microwave Four had worked in the room where microwave popcorn flavoring agents were mixed, and four had popcorn flavoring agents were mixed, and four had worked only in the microwave popcorn packaging worked only in the microwave popcorn packaging area.area.

Diagnosis: Diagnosis: Bronchiolitis obliteransBronchiolitis obliterans Initiated by damage to the epithelium of Initiated by damage to the epithelium of

the small airways, progressing to the small airways, progressing to inflammation of these airways (and inflammation of these airways (and frequently of adjacent alveoli)frequently of adjacent alveoli)

Clinical consequence: irreversible Clinical consequence: irreversible airway obstructionairway obstruction

Bronchiolitis obliteransBronchiolitis obliterans

Bronchiolitis has been associated with Bronchiolitis has been associated with irritant gases, notably oxides of nitrogenirritant gases, notably oxides of nitrogen

But also chlorine, phosgene, hydrogen But also chlorine, phosgene, hydrogen sulfide, sulfur dioxidesulfide, sulfur dioxide

Organic and inorganic dustsOrganic and inorganic dusts

Bronchiolitis ObliteransBronchiolitis Obliterans

A number of cases in industries not A number of cases in industries not previously associated with this disease, previously associated with this disease, eg eg Battery workers (thionyl chloride fumes)Battery workers (thionyl chloride fumes) Workers who sprays paints onto textiles Workers who sprays paints onto textiles

with polyamide-amide dyes), etcwith polyamide-amide dyes), etc Most often: a cluster of cases leads to Most often: a cluster of cases leads to

investigation investigation

The InvestigationThe Investigation

The Missouri Department of Health The Missouri Department of Health asks NIOSH to investigate.asks NIOSH to investigate.

Microwave Popcorn PlantMicrowave Popcorn Plant

The plant:The plant: A flavor-mixing roomA flavor-mixing room A quality control room for popping sample A quality control room for popping sample

productproduct A maintenance shopA maintenance shop Packaging lines where microwavable bags Packaging lines where microwavable bags

were filled with popcorn and flavorings, were filled with popcorn and flavorings, packaged and boxedpackaged and boxed

FlavoringsFlavorings

Ingredients of the flavorings included soybean oil, Ingredients of the flavorings included soybean oil, salt, butter flavoring, and coloring agents.salt, butter flavoring, and coloring agents.

In the mixing room, one worker per shift opened the In the mixing room, one worker per shift opened the lid of an oil tank that was heated to approximately lid of an oil tank that was heated to approximately 130130ºF (54ºC) and added flavorings in batch ºF (54ºC) and added flavorings in batch operations.operations.

Flavoring mixture then pumped into heated holding Flavoring mixture then pumped into heated holding tanks above the microwave-popcorn packaging lines.tanks above the microwave-popcorn packaging lines.

On the packaging lines: kernel popcorn and flavoring On the packaging lines: kernel popcorn and flavoring mixture added to the microwavable bags by a mixture added to the microwavable bags by a machine operator; bags then sealed, labeled and machine operator; bags then sealed, labeled and boxed; boxes stacked on pallets.boxed; boxes stacked on pallets.

The Plant (Cont’d)The Plant (Cont’d)

Areas of the plant physically separate Areas of the plant physically separate from the microwave popcorn from the microwave popcorn production area:production area: The warehouseThe warehouse The bag-printing areaThe bag-printing area The line where unflavored kernel popcorn The line where unflavored kernel popcorn

was packaged (in polyethylene bags)was packaged (in polyethylene bags) The offices where management and clerical The offices where management and clerical

activities were performedactivities were performed

Air samplesAir samples

Analysis of air samples from the mixing Analysis of air samples from the mixing room:room: More than More than 100 volatile organic compounds100 volatile organic compounds

There were no known occupational causes of There were no known occupational causes of bronchiolitis obliterans identified among bronchiolitis obliterans identified among these compounds or in the plant at large.these compounds or in the plant at large.

Diacetyl (2, 3-butanedione), a ketone with Diacetyl (2, 3-butanedione), a ketone with butter-flavor characteristics, was the butter-flavor characteristics, was the predominant compound isolated from air predominant compound isolated from air samples.samples.

The ChallengeThe Challenge

Specific cases of a rare disease have Specific cases of a rare disease have been identifiedbeen identified

Their only common element: working at Their only common element: working at the same plantthe same plant

No industrial accidentNo industrial accident No known toxicant at the plantNo known toxicant at the plant

The ChallengeThe Challenge

Lack of evidence re:effects of chemicals Lack of evidence re:effects of chemicals is is

The PlanThe Plan

Determine condition of other workers at Determine condition of other workers at the plantthe plant

Study what substance most likely Study what substance most likely associated with symptomsassociated with symptoms

Medical SurveyMedical Survey

Trained interviewers administered a Trained interviewers administered a standardized questionnaire about standardized questionnaire about respiratory, mucous-membrane, and respiratory, mucous-membrane, and constitutional symptoms and work constitutional symptoms and work historyhistory

Compared responses with data from Compared responses with data from identical questions on the third National identical questions on the third National Health and Nutrition Examination Health and Nutrition Examination Survey (NHANES III)Survey (NHANES III)

Medical Survey (Cont’d)Medical Survey (Cont’d)

Spirometry and measurement of carbon Spirometry and measurement of carbon monoxide diffusing capacity; monoxide diffusing capacity;

Comparisons:Comparisons: spirometric reference values NHANES III spirometric reference values NHANES III

Assessment of ExposureAssessment of Exposure

Characterized job-specific exposure to diacetyl, by Characterized job-specific exposure to diacetyl, by testing air samples from various areas in the plant.testing air samples from various areas in the plant.

Examined respirable dust samples from employees’ Examined respirable dust samples from employees’ breathing zone and various areas in the plant.breathing zone and various areas in the plant.

Estimated the cumulative exposure for each Estimated the cumulative exposure for each participant by summing the products of the time participant by summing the products of the time spent at each job and the mean exposure in that job spent at each job and the mean exposure in that job area. (four quartiles according to rank order of area. (four quartiles according to rank order of increasing cumulative exposure to diacetyl).increasing cumulative exposure to diacetyl).

Characteristics of WorkersCharacteristics of Workers

97 worked in the microwave popcorn 97 worked in the microwave popcorn production area of the plant.production area of the plant.

Of these:Of these: 6 reported having changed job assignments 6 reported having changed job assignments

at the plant because of breathing at the plant because of breathing difficultiesdifficulties

ExposureExposure

Levels of diacetyl exposure:Levels of diacetyl exposure: Mixing room employees exposed to roughly Mixing room employees exposed to roughly

800 times the level to which workers in the 800 times the level to which workers in the internal reference group were exposed,internal reference group were exposed,

55 times that to which the quality-control 55 times that to which the quality-control and maintenance workers were exposed,and maintenance workers were exposed,

15 times that to which workers on the 15 times that to which workers on the microwave popcorn packaging lines were microwave popcorn packaging lines were exposed.exposed.

Bronchiolitis Obliterans in Bronchiolitis Obliterans in Microwave-Popcorn WorkersMicrowave-Popcorn Workers

Exposure Exposure Outside the Popcorn PlantOutside the Popcorn Plant

Farming (40%)Farming (40%) Grain dust (32%)Grain dust (32%) Irritant gases (14%)Irritant gases (14%) Nitrogen oxides (8%)Nitrogen oxides (8%)

Exposure to DiacetylExposure to Diacetyl

Bronchiolitis Obliterans in Bronchiolitis Obliterans in Microwave-Popcorn WorkersMicrowave-Popcorn Workers

Prevalence of Health-Related Prevalence of Health-Related OutcomesOutcomes Ratio of observed to expected prevalence of Ratio of observed to expected prevalence of

health-related outcomes, with expected rates health-related outcomes, with expected rates based on rates from NHANES III, after based on rates from NHANES III, after adjustment for age and smoking status; the adjustment for age and smoking status; the current workers reported:current workers reported:

2.6 times the prevalence of chronic cough2.6 times the prevalence of chronic cough 2.6 times the prevalence of exertional shortness of 2.6 times the prevalence of exertional shortness of

breathbreath 3 times the prevalence of wheezing (other than 3 times the prevalence of wheezing (other than

wheezing due to colds)wheezing due to colds)

Prevalence of Health-Related Prevalence of Health-Related Outcomes (Cont’d)Outcomes (Cont’d) Overall, current employees had 3.3 times the Overall, current employees had 3.3 times the

expected rate of airway obstruction. The expected rate of airway obstruction. The prevalence of airway obstruction increased prevalence of airway obstruction increased with increasing age in both current and with increasing age in both current and former smokers at the plant and especially in former smokers at the plant and especially in workers who had never smoked:workers who had never smoked:

The prevalence ratios in this subgroup were 11.4 The prevalence ratios in this subgroup were 11.4 among workers 40 years old or older and 3.8 among workers 40 years old or older and 3.8 among those younger than 40.among those younger than 40.

Relation between Exposures Relation between Exposures and Health-Related Outcomesand Health-Related Outcomes Workers in the microwave-popcorn Workers in the microwave-popcorn

production areas (including quality-control production areas (including quality-control and maintenance workers): significantly and maintenance workers): significantly higher rates of exertional shortness of breath, higher rates of exertional shortness of breath, regular trouble with breathing, a combination regular trouble with breathing, a combination of two or more respiratory symptoms, of two or more respiratory symptoms, unusual fatigue, and any systemic symptoms unusual fatigue, and any systemic symptoms than minimally exposed workers in other than minimally exposed workers in other areas of the plant. The rate of rashes or other areas of the plant. The rate of rashes or other skin problems since the date of hire was also skin problems since the date of hire was also significantly higher among workers in the significantly higher among workers in the microwave-popcorn production areas than microwave-popcorn production areas than among those in other areas.among those in other areas.

Airway ObstructionAirway Obstruction

The prevalence of airway obstruction The prevalence of airway obstruction increased with increasing cumulative increased with increasing cumulative exposure to diacetyl.exposure to diacetyl.

Of other indexes of exposure, working Of other indexes of exposure, working in the quality-control room at the plant in the quality-control room at the plant was significantly associated with airway was significantly associated with airway obstruction, after adjustment for age obstruction, after adjustment for age and smoking status.and smoking status.

Airway Obstruction (Cont’d)Airway Obstruction (Cont’d)

The combination of fixed airway obstruction The combination of fixed airway obstruction with normal findings on chest radiography is with normal findings on chest radiography is best explained by bronchiolitis obliterans, best explained by bronchiolitis obliterans, which had been recognized in 8 former which had been recognized in 8 former workers.workers.

In contrast to most examples of occupational In contrast to most examples of occupational constrictive bronchiolitis obliterans, neither constrictive bronchiolitis obliterans, neither the former workers nor the current workers the former workers nor the current workers reported a distinct episode of overexposure reported a distinct episode of overexposure that preceded the onset of symptoms.that preceded the onset of symptoms.

Severity of SymptomsSeverity of Symptoms

Unlike occupational asthma, no Unlike occupational asthma, no temporal relation existed between temporal relation existed between working at the plant and the severity of working at the plant and the severity of symptoms over the course of the symptoms over the course of the workday or workweek.workday or workweek.

Thus, the association of this endemic Thus, the association of this endemic disease with exposures in the workplace disease with exposures in the workplace was largely unsuspected by the workers, was largely unsuspected by the workers, their physicians and plant managers.their physicians and plant managers.

““Healthy-Worker Effect”Healthy-Worker Effect”

Cross-sectional surveys of occupational hazards Cross-sectional surveys of occupational hazards underestimate health-related outcomes because of the underestimate health-related outcomes because of the ““Healthy-Worker EffectHealthy-Worker Effect.”.”

In this plant, 8 former workers were known to have In this plant, 8 former workers were known to have left their jobs because of lung disease, thus leaving a left their jobs because of lung disease, thus leaving a healthier workforce that did not carry the entire healthier workforce that did not carry the entire burden of disease.burden of disease.

Workers who changed assignments because of Workers who changed assignments because of respiratory problems were included in analyses of respiratory problems were included in analyses of current exposure as having these problems in their current exposure as having these problems in their current assignments, an assumption that may be current assignments, an assumption that may be inaccurate.inaccurate.

Analyses of cumulative exposure in relation to Analyses of cumulative exposure in relation to indexes of airway obstruction partially correct for indexes of airway obstruction partially correct for this limitation.this limitation.

Diacetyl levelsDiacetyl levels

In inhalation studies, butter-flavoring vapors In inhalation studies, butter-flavoring vapors producing diacetyl levels of 352 ppm damaged producing diacetyl levels of 352 ppm damaged respiratory epithelium in the airways of rats.respiratory epithelium in the airways of rats.

NIOSH scientists chose this exposure level as one NIOSH scientists chose this exposure level as one similar to that of possible peak levels in the space similar to that of possible peak levels in the space above the heated oil within the mixing or holding above the heated oil within the mixing or holding tanks in the popcorn plant.tanks in the popcorn plant.

A peak diacetyl level of 1230 ppm was later measured A peak diacetyl level of 1230 ppm was later measured in this space in a tank holding the same butter in this space in a tank holding the same butter flavoring tested in the animal studies.flavoring tested in the animal studies.

Diacetyl levels (Cont’d)Diacetyl levels (Cont’d)

Damage in the rats extended below the basement Damage in the rats extended below the basement membrane of sloughed respiratory epithelium, membrane of sloughed respiratory epithelium, suggesting that repair would probably involve airway suggesting that repair would probably involve airway fibrosis.fibrosis.

These preliminary findings in animals suggest that a These preliminary findings in animals suggest that a volatile ingredient in the butter flavoring is a volatile ingredient in the butter flavoring is a biologically plausible cause of the respiratory effects biologically plausible cause of the respiratory effects seen in the workers in the popcorn plant.seen in the workers in the popcorn plant.

Support for this hypothesis comes from the findings Support for this hypothesis comes from the findings of a health-hazard investigation at a company that of a health-hazard investigation at a company that mixed flavorings in cornstarch for the baking mixed flavorings in cornstarch for the baking industry.industry.

RecommendationsRecommendations

The use of air-purifying respirators with The use of air-purifying respirators with cartridges that filter organic vapors and cartridges that filter organic vapors and particulates to decrease exposures to particulates to decrease exposures to flavorings and isolation of ventilation in the flavorings and isolation of ventilation in the mixing room from that in other areas of the mixing room from that in other areas of the plant.plant.

Workers with symptoms or obstructive Workers with symptoms or obstructive abnormalities advised to seek medical counsel abnormalities advised to seek medical counsel regarding diagnosis, smoking cessation, regarding diagnosis, smoking cessation, immunization, and the advisability of immunization, and the advisability of continued exposure in the workplace, with or continued exposure in the workplace, with or without respiratory protection.without respiratory protection.

Also:Also:

What else was new in that study?What else was new in that study? Studied symptoms throughout the plant, Studied symptoms throughout the plant,

identifying subclinical diseaseidentifying subclinical disease If this = smoldering bronchiolitis If this = smoldering bronchiolitis

obliterans, even more workers may be at obliterans, even more workers may be at risk for progressive pulmonary diseaserisk for progressive pulmonary disease

More widespread control measures may be More widespread control measures may be needed than simply identification of needed than simply identification of clusters of cases (eg in industries with clusters of cases (eg in industries with irritant dusts, gases, fumes) irritant dusts, gases, fumes)

ConclusionsConclusions

Alarm sounded by astute clinicianAlarm sounded by astute clinician Investigation did not stop at “no known Investigation did not stop at “no known

toxicant”toxicant” Results: will help protect the help of Results: will help protect the help of

workers workers