Paul D. Blanc

Diagnosis and Management of Work-Related Asthma: American College of Chest Physicians Consensus Statement

BACKGROUND A previous American College of Chest Physicians Consensus Statement on asthma in the workplace was published in 1995. The current Consensus Statement updates the previous one based on additional research that has been published since then, including findings relevant to preventive measures and work-exacerbated asthma (WEA). METHODS A panel of experts, including allergists, pulmonologists, and occupational medicine physicians, was convened to develop this Consensus Document on the diagnosis and management of work-related asthma (WRA), based in part on a systematic review, that was performed by the University of Alberta/Capital Health Evidence-Based Practice and was supplemented by additional published studies to 2007. RESULTS The Consensus Document defined WRA to include occupational asthma (ie, asthma induced by sensitizer or irritant work exposures) and WEA (ie, preexisting or concurrent asthma worsened by work factors). The Consensus Document focuses on the diagnosis and management of WRA (including diagnostic tests, and work and compensation issues), as well as preventive measures. WRA should be considered in all individuals with new-onset or worsening asthma, and a careful occupational history should be obtained. Diagnostic tests such as serial peak flow recordings, methacholine challenge tests, immunologic tests, and specific inhalation challenge tests (if available), can increase diagnostic certainty. Since the prognosis is better with early diagnosis and appropriate intervention, effective preventive measures for other workers with exposure should be addressed. CONCLUSIONS The substantial prevalence of WRA supports consideration of the diagnosis in all who present with new-onset or worsening asthma, followed by appropriate investigations and intervention including consideration of other exposed workers.

Dose-dependent cigarette smoking-related inflammatory responses in healthy adults

The aim of this study was to determine the dose-response relationship between cigarette smoke exposure and pulmonary cell and cytokine concentrations in bronchoalveolar lavage (BAL). BAL cells and BAL supernatant concentrations of tumour necrosis factor-alpha (TNF alpha), interleukin (IL)-1 beta, IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 from 14 healthy smokers and 16 healthy nonsmokers were quantified. Statistically greater concentrations of neutrophils, macrophages, IL-1 beta, IL-6, IL-8 and MCP-1 were observed among smokers compared with nonsmokers (p < or = 0.0007 in all cases). Cigarette smoking, categorized ordinally as: less than one pack, one pack, or greater than one pack per day, was predictive of BAL macrophages (p < 0.0001), neutrophils (p = 0.015), IL-1 beta (p < 0.001) and IL-8 (p = 0.02). We conclude that concentrations of macrophages, neutrophils, IL-1 beta and IL-8 are elevated in the pulmonary microenvironment of smokers in a cigarette dose-dependent manner. Based on the present findings, we would caution against simple analyses that treat current smokers as a homogeneous group and which do not account for smoking intensity.

Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II)

BACKGROUND The role of exposure to substances in the workplace in new-onset asthma is not well characterised in population-based studies. We therefore aimed to estimate the relative and attributable risks of new-onset asthma in relation to occupations, work-related exposures, and inhalation accidents. METHODS We studied prospectively 6837 participants from 13 countries who previously took part in the European Community Respiratory Health Survey (1990-95) and did not report respiratory symptoms or a history of asthma at the time of the first study. Asthma was assessed by methacholine challenge test and by questionnaire data on asthma symptoms. Exposures were defined by high-risk occupations, an asthma-specific job exposure matrix with additional expert judgment, and through self-report of acute inhalation events. Relative risks for new onset asthma were calculated with log-binomial models adjusted for age, sex, smoking, and study centre. FINDINGS A significant excess asthma risk was seen after exposure to substances known to cause occupational asthma (Relative risk=1.6, 95% CI 1.1-2.3, p=0.017). Risks were highest for asthma defined by bronchial hyper-reactivity in addition to symptoms (2.4, 1.3-4.6, p=0.008). Of common occupations, a significant excess risk of asthma was seen for nursing (2.2, 1.3-4.0, p=0.007). Asthma risk was also increased in participants who reported an acute symptomatic inhalation event such as fire, mixing cleaning products, or chemical spills (RR=3.3, 95% CI 1.0-11.1, p=0.051). The population-attributable risk for adult asthma due to occupational exposures ranged from 10% to 25%, equivalent to an incidence of new-onset occupational asthma of 250-300 cases per million people per year. INTERPRETATION Occupational exposures account for a substantial proportion of adult asthma incidence. The increased risk of asthma after inhalation accidents suggests that workers who have such accidents should be monitored closely.

How much adult asthma can be attributed to occupational factors

PURPOSE Many occupational factors can cause asthma or reactivate preexisting disease. We carried out a critical review and synthesis of the available literature to estimate the proportion of adult asthma that is attributable to workplace factors. METHODS We reviewed published citations from 1966 through May 1999 as well as recent abstracts of studies providing risk estimates for asthma among various occupations. We extracted published attributable risk estimates, derived others from published data, and extrapolated estimates from the incidence rates of occupational asthma. We used a semiquantitative score to rank studies based on their characteristics. RESULTS We obtained 43 attributable risk estimates from 19 different countries: 23 were published estimates, 8 were derived from published data, and 12 were extrapolated from incidence data. The median value for the attributable risk of occupationally associated asthma was 9%(25th to 75th interquartile range: 5% to 19%). The derived estimates (median attributable risk = 25%) were significantly greater than published values (median = 9%, P = 0.002), whereas the extrapolated estimates were significantly lower (median = 5%, P = 0.04). The 12 highest scored studies based on their characteristics yielded a median risk estimate of 15%. CONCLUSION Occupational factors are associated with about 1 in 10 cases of adult asthma, including new onset disease and reactivation of preexisting asthma.

The occupational burden of chronic obstructive pulmonary disease

Although chronic obstructive pulmonary disease (COPD) is attributed predominantly to tobacco smoke, occupational exposures are also suspected risk factors for COPD. Estimating the proportion of COPD attributable to occupation is thus an important public health need. A randomly selected sample of 2,061 US residents aged 55–75 yrs completed telephone interviews covering respiratory health, general health status and occupational history. Occupational exposure during the longest-held job was determined by self-reported exposure to vapours, gas, dust or fumes and through a job exposure matrix. COPD was defined by self-reported physicians diagnosis. After adjusting for smoking status and demography, the odds ratio for COPD related to self-reported occupational exposure was 2.0 (95% confidence interval (CI) 1.6–2.5), resulting in an adjusted population attributable risk (PAR) of 20% (95% CI 13–27%). The adjusted odds ratio based on the job exposure matrix was 1.6 (95% CI 1.1–2.5) for high and 1.4 (95% CI 1.1–1.9) for intermediate probability of occupational dust exposure; the associated PAR was 9% (95% CI 3–15%). A narrower definition of COPD, excluding chronic bronchitis, was associated with a PAR based on reported occupational exposure of 31% (95% CI 19–41%). Past occupational exposures significantly increased the likelihood of chronic obstructive pulmonary disease, independent of the effects of smoking. Given that one in five cases of chronic obstructive pulmonary disease may be attributable to occupational exposures, clinicians and health policy-makers should address this potential avenue of chronic obstructive pulmonary disease causation and its prevention.

Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature.

An increasing segment of the U.S. population is seeking alternatives to traditional Western allopathic medicine. In 1990, Americans made an estimated 425 million visits to providers of unconventional therapies [1]. One particularly popular alternative is herbal medication. Herbal medicines are promoted as more natural and therefore safer than conventional over-the-counter and prescription medicines, but many may be more dangerous than conventional pharmaceutical agents [2]. Both over-the-counter and prescription medicines in the United States must be extensively tested and certified before the Food and Drug Administration approves them for indicated uses. In contrast, herbal preparations are not subjected to such scrutiny before being promoted and sold. Pennyroyal is one widely available herbal medicine that can be life threatening after ingestion. Pennyroyal, an herb consisting of the leaves of either Mentha pulegium or Hedeoma pulegioides, primarily contains pulegone (Figure 1) plus smaller amounts of several other monoterpenes that are encountered in mint species [3]. Pennyroyal is commonly available in health food stores. Since Roman times, herbalists have recommended the herb as an abortifacient [4]. Although no evidence supports its efficacy in this regard [5], many herbal books continue to cite the use of pennyroyal for this purpose [6, 7], despite reports of centrilobular hepatic necrosis and death in connection with its use [8-11]. Pennyroyal is also advocated as a pesticide, primarily for controlling fleas on domestic pets and in the home [12]. Hepatotoxicity and other cellular damage have been reported in a household pet treated with pennyroyal oil [13]. Figure 1. Structures of the major monoterpene in pennyroyal, (R)-(+)-pulegone, and its major proximate toxic metabolite, menthofuran. Pennyroyal poisoning continues to occur regularly. Although pennyroyal ingestion can be fatal, cases of poisoning have only been sporadically documented in the modern medical literature, and none has involved the use of recent analytic techniques to measure pennyroyal metabolite levels. We report four recent cases of pennyroyal toxicity, two of which had laboratory confirmation of pulegone or its major toxic metabolite menthofuran [14]. We also review all of the published clinical case data from earlier reports and place our four cases in the context of reported signs and symptoms of toxicity. Methods Quantification of Pulegone and Menthofuran Plasma samples were acidified and extracted with diethylether after internal standards were added. To identify and quantify pulegone and menthofuran [14, 15], we compared their gas chromatographic retention times and mass spectra with those of known standards. Gas chromatographic analysis was done on a Hewlett-Packard (Palo Alto, California) Model 5980. Chromatography was done on a 30 m 0.320 mm Wall Coated Open Tubular DB-5 fused silica capillary column (J & W Scientific, Folsom, California). Electron-impact mass spectrometry was done using a VG-7070H double-focusing instrument (Manchester, United Kingdom) that was equipped with a Hewlett-Packard Model 5980 Series II gas chromatograph and was electronically linked to a Mass Spectrometry Service data system (Manchester, United Kingdom). Identification of Protein-Bound Pennyroyal Metabolites by Western Blot Analysis Liver microsomes were prepared from a liver sample obtained from patient 1 and from a human liver sample obtained from the University of Washington School of Pharmacy Liver Bank. To provide a positive control, a portion of the latter sample was incubated with menthofuran and an NADPH (reduced nicotinamide adenine dinucleotide phosphate)-regenerating system. Microsomal proteins were subjected to electrophoresis in sodium dodecyl sulfate-polyacrylamide gels, and the protein bands were transferred to nitrocellulose solid support. Protein adducts were detected using a primary antibody obtained from rabbits immunized with chemically synthesized oxidative metabolites of menthofuran coupled to metallothionein and with a secondary antibody of horseradish peroxidase-conjugated goat antirabbit IgG (Pierce Chemical Co., Rockford, Illinois). The membranes were developed using 0.004% nickel chloride, 0.0075% hydrogen peroxide, and 0.05% 3,3-diaminobenzidine tetrahydrochloride. Poison Center Reporting We selected patients by reviewing all cases involving pennyroyal ingestion for which the San Francisco Bay Area Regional Poison Control Center was primarily consulted during a 2-year period. We included all medically treated or symptomatic cases and excluded two other cases initially reported to a collaborating regional poison control center for which our service provided a secondary consultation. All data were collected by telephone and were recorded on a standard American Association Poison Control Center Cooperative Poison Center report form at the time of the initial consultation. The poison information specialist obtained all pertinent information available. Follow-up contact by telephone was continued until the clinical outcome was determined. The San Francisco Poison Control Center receives an average of 60 000 consultations each year [16]. Literature Review We identified case reports by searching MEDLINE and Index Medicus and by reviewing the reference citations of all available publications. One reference citation was supposedly a case report of pennyroyal poisoning; however, we later reviewed the original report and discovered that the case did not involve poisoning and appears to have been cited in error [17]. Only 7 of the 18 cases are from the modern medical literature; the others were reported before 1905. The cases reported before 1905 are less well documented, but we did not exclude cases for this reason. Case Reports Case 1 A 24-year-old woman repeatedly ingested pennyroyal herbal extract (pennyroyal herb, 48% to 56% in an alcohol base) and black cohosh root (Cimicifuga racemosa) extract for 2 weeks in an attempt to induce an abortion. When this was unsuccessful, she ingested additional unknown amounts of pennyroyal herbal extract and black cohosh root extract over a short period. Soon after, abdominal cramps, chills, vomiting, and syncope developed, and the patient had difficulty walking. She was placed in a cold bath 7 hours after the acute ingestion and began to manifest rigors that her roommate interpreted as a seizure. Paramedics found the patient in cardiopulmonary arrest at a time estimated to be 7.5 hours after the acute ingestion. The patient was intubated, and then cardiopulmonary resuscitation was initiated and continued for 22 minutes until the patient arrived at the hospital. On arrival at the emergency department, the patients heart rate was 120 beats/min and her blood pressure was 70/40 mm Hg while she received maximal dopamine. Her pupils were fixed and dilated. The physical examination showed coma and a rigid abdomen. A computed tomographic scan of the abdomen suggested a possible ruptured ectopic pregnancy. Initial laboratory values were the following: sodium level, 157 mmol/L; potassium level, 5.7 mmol/L; chlorine level, 107 mmol/L; bicarbonate level, 8 mmol/L; blood urea nitrogen level, 5.0 mmol/L; creatinine level, 221 mol/L; glucose level, 6.8 mmol/L; lactic acid level, 21.0 mmol/L; leukocyte count, 37.3 109/L; hemoglobin level, 89 g/L; hematocrit, 0.28; platelet count, 256 109/L; albumin level, 27 g/L; total bilirubin level, 5.1 mol/L; aspartate aminotransferase level, 0.82 kat/L; lactate dehydrogenase level, 3.54 kat/L; amylase level, 2.35 kat/L; prothrombin time, 23 seconds; partial prothrombin time, 68 seconds; and international normalized ratio, 4.1. A quantitative plasma human chorionic gonadotropin level indicated that the patient was 1 to 3 months pregnant. Arterial blood gas values (measured while the patient received 100% O2 by endotracheal tube) were the following: pH, 6.61; Pco 2, 23 mm Hg; and Po 2, 503 mm Hg. A toxicology screen was negative for alcohol, acetaminophen, and salicylates. Laboratory values 36 hours after the acute ingestion were notable for the aspartate aminotransferase level (44.53 kat/L), the alanine aminotransferase level (29.12 kat/L), and the lactate dehydrogenase level (68.18 kat/L). Throughout the initial 12 hours of hospitalization, the patients course was marked by hemodynamic shock, decreasing hematocrit, and a clinical picture consistent with disseminated intravascular coagulation. During hospitalization, the patient received 10 units of packed red blood cells and multiple units of fresh frozen plasma. Exploratory laparotomy showed a hemorrhagic, right-sided ectopic pregnancy with indications of superinfection. A substantial amount of old blood, not otherwise quantified, was found. The pregnancy was not ruptured, but there was evidence of bleeding from the end of the tube. No active bleeding was seen during surgery. A computed tomographic scan of the head was consistent with anoxic encephalopathy. The patient remained unresponsive to all stimuli. Life support was withdrawn, and the patient died 46 hours after the acute pennyroyal ingestion. Other than the anticipated brain and uterine findings, the most notable abnormalities at autopsy were found in the liver. The substantial centrilobular degeneration and necrosis of the hepatic cells were consistent with a specific toxic insult. Diffuse degenerative changes involving the proximal tubules of the kidney were also noted. The pathologist concluded that the cause of death was multiorgan failure and anoxic encephalopathy secondary to ingestion of pennyroyal and black cohosh. Blood from the heart, collected at autopsy 26 hours after death, was tested for the presence of pulegone and menthofuran. The pennyroyal and black cohosh herbal extracts that the patient had ingested were also tested for the presence of pulegone and menthofuran (Table 1). Table 1. Laboratory Values of Pennyroyal Metabolites in Case 1* Po

Lifetime environmental tobacco smoke exposure and the risk of chronic obstructive pulmonary disease.

BackgroundExposure to environmental tobacco smoke (ETS), which contains potent respiratory irritants, may lead to chronic airway inflammation and obstruction. Although ETS exposure appears to cause asthma in children and adults, its role in causing COPD has received limited attention in epidemiologic studies.MethodsUsing data from a population-based sample of 2,113 U.S. adults aged 55 to 75 years, we examined the association between lifetime ETS exposure and the risk of developing COPD.Participants were recruited from all 48 contiguous U.S. states by random digit dialing. Lifetime ETS exposure was ascertained by structured telephone interview. We used a standard epidemiologic approach to define COPD based on a self-reported physician diagnosis of chronic bronchitis, emphysema, or COPD.ResultsHigher cumulative lifetime home and work exposure were associated with a greater risk of COPD. The highest quartile of lifetime home ETS exposure was associated with a greater risk of COPD, controlling for age, sex, race, personal smoking history, educational attainment, marital status, and occupational exposure to vapors, gas, dusts, or fumes during the longest held job (OR 1.55; 95% CI 1.09 to 2.21). The highest quartile of lifetime workplace ETS exposure was also related to a greater risk of COPD (OR 1.36; 95% CI 1.002 to 1.84). The population attributable fraction was 11% for the highest quartile of home ETS exposure and 7% for work exposure.ConclusionETS exposure may be an important cause of COPD. Consequently, public policies aimed at preventing public smoking may reduce the burden of COPD-related death and disability, both by reducing direct smoking and ETS exposure.

Asthma caused by occupational exposures is common – A systematic analysis of estimates of the population-attributable fraction

BackgroundThe aim of this paper is to highlight emerging data on occupational attributable risk in asthma. Despite well documented outbreaks of disease and the recognition of numerous specific causal agents, occupational exposures previously had been relegated a fairly minor role relative to other causes of adult onset asthma. In recent years there has been a growing recognition of the potential importance of asthma induced by work-related exposuresMethodsWe searched Pub Med from June 1999 through December 2007. We identified six longitudinal general population-based studies; three case-control studies and eight cross-sectional analyses from seven general population-based samples. For an integrated analysis we added ten estimates prior to 1999 included in a previous review.ResultsThe longitudinal studies indicate that 16.3% of all adult-onset asthma is caused by occupational exposures. In an overall synthesis of all included studies the overall median PAR value was 17.6%.ConclusionClinicians should consider the occupational history when evaluating patients in working age who have asthma. At a societal level, these findings underscore the need for further preventive action to reduce the occupational exposures to asthma-causing agents.

Health and socioeconomic impact of work-related asthma

There is accumulating evidence that the workplace environment contributes significantly to the general burden of asthma. The purpose of this review is to explore the respiratory health and socioeconomic consequences of work-related asthma by addressing a series of controversial issues: 1) what is the natural history of occupational asthma and in what ways does ongoing exposure to the causal agent impact clinical outcomes?; 2) how does the natural history of irritant-induced asthma differ in its health outcomes from immunologically-mediated occupational asthma?; 3) do working conditions have a significant impact on asthma regardless of the aetiology of the disease?; 4) what is the scope of work disability from work-related-asthma in social and economic terms?; 5) what is the clinicians role in reducing the respiratory health consequences of work-related asthma? 6) to what extent do existing compensation and other social insurance schemes successfully address occupational asthma and work-aggravated asthma?

The work impact of asthma and rhinitis: Findings from a population-based survey

Asthma and rhinitis are common chronic conditions that affect adults of working age. Little is known about their relative impacts on work loss and decreased productivity. Using random digit telephone dialing, we carried out a population-survey of adults in Northern California aged 18-50 years. We interviewed 125 persons with asthma (with or without concomitant rhinitis) and 175 persons with rhinitis alone. Study eligibility was based on subject report of a physicians diagnosis of asthma and/or a rhinitis-related condition. Any adult labor force participation since condition onset was lower among those with asthma (88%) than among those with rhinitis alone (97%) (P = 0.002). In contrast, among those still employed, decreased job effectiveness was more frequently reported in the rhinitis group (43 of 121; 36%) compared to those with asthma (14 of 72; 19%) (P = 0.02). Condition-attributed lost work was common in both groups, with more than 20% reporting one or more complete or partial work days lost in the 4 weeks previous to interview. Taking into account age, gender, race, and smoking status, those with asthma were more likely to have no labor force participation after diagnosis (OR = 3.0; 95% CI 1.1-7.7) and less likely to report decreased job effectiveness among those remaining employed (OR = 0.4; 95% CI 0.2-0.9). Excluding subjects from the rhinitis group most likely to have unreported asthma based on past medication use had little impact on these associations. Both asthma and rhinitis negatively affect work productivity. Those with asthma are less likely to be employed at all, while among those remaining on the job, rhinitis is a more potent cause of decreased work effectiveness. The economic impact of asthma and rhinitis and related conditions may be under-appreciated.