The “exposure window”

We used the hospitalization database to identify all BC residents aged 18 to 55 years old who had been discharged from an episode of hospitalization with a main diagnosis of asthma (ICD-9: 493.xx, ICD-10: J45, J46). A previous chart review study showed that the main diagnosis of asthma in a discharge record had a sensitivity of 87% and a positive predictive value of 90%. We excluded the pediatric patient population because in Canada Pharmacy pediatricians can act as both generalists and specialists.

Patients were categorized as receiving primary care if they had had at least one outpatient service record, with asthma as the reason for the service, generated by a GP within 2 months of discharge from the index hospitalization, and had no code generated by any specialist during this time window. Patients were considered to be under secondary care if they had at least one outpatient service record for asthma generated by an internal medicine, a respiratory medicine, or an allergy/clinical immunology specialist. Of note, in Canada, where a publicly funded health-care system is in place, all internists practice as consultants, providing secondary care and requiring a referral from a general practitioner.

The “exposure window” of 2 months was chosen to cover the wait time for visiting a specialist and to account for situations in which the patient sought care sometime after finishing the medications provided on the discharge day (usually supplied for 30 days). Individuals not satisfying these exposure definitions were excluded from this analysis. An index date was assigned as the 60th day after discharge from the index hospitalization. 

Similar to the concept of “intention-to-treat” analysis, in the main analysis we retained the individuals’ exposure status for the entire follow-up period regardless of the subsequent changes in the type of care. Each individual could potentially contribute more than one index hospitalization and its corresponding follow-up period, provided that such follow-up times did not overlap.

Patients were followed for up to 12 months after the index date. Patients who exited the provincial coverage and those who died prior to 12 months after the index date were excluded from this analysis.

A critical issue in comparing the outcomes of primary vs secondary care is to adjust for the case mix, because patients under secondary care are more likely to have more severe asthma. To rigorously adjust for the case mix, we created a propensity-score-matched cohort.

Respiratory assessment

Due to the established differences between Feno for atopic and nonatopic subjects, separate multivariate regression models were constructed for both atopic and nonatopic individuals using transformed Feno values as the outcome variable. Factors that had a significance level of at least p < 0.1 from univariate analyses were included in these models. These were age, height, gender, history of PDA ever, current PDA, recent wheeze, DRS, current smoking, and atopy. 

Respiratory assessment

Variables in all models were excluded in a backward step-wise fashion. Regression coefficients were log transformed back, and are reported as the fold difference between categorical variables, eg, symptoms, or fold increase per unit change in continuous variables. Feno levels, DRS, and blood eosinophil values are reported as geometric means with 95% confidence intervals (CIs). All analyses were performed using SPSS version 10.0.7 (SPSS; Chicago, IL).

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Two hundred forty-six study subjects underwent a respiratory assessment; however, only 115 attended the hospital where Feno concentrations were measured. These subjects are included in the analyses for this article. There were no differences between subjects with and without Feno measurements for age, gender, and proportion with asthma, atopy, and PD₂₀ < 7.8. Of the 115 subjects with Feno measurements, 77 were women and the mean age was 41 years (range, 31 to 56 years). The men (mean age, 43 years; SD 4) were older than the women (mean age, 39 years; SD 4) [p < 0.001]. Subject details are presented separately for men and women in Table 1.

Feno measurements of two asthmatics treated with regular inhaled steroids were 10.9 ppb and 11.8 ppb, respectively, and due to known effects of inhaled corticosteroids on Feno,²¹ these data were not included in analyses. SPT was performed in all of the remaining 113 individuals, bronchial challenge in 110 patients, spirometry in 112 patients, and eosinophil count in 112 patients. Seventy-eight study subjects (68%) were atopic, 31 subjects (26%) had a history of PDA ever, 20 subjects (18%) had current PDA, 25 subjects (22%) currently smoked, 19 subjects (17%) reported wheeze in the past 12 months, and 19 subjects (17%) had increased AR.

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Health and Care: Solvent extraction method

 Health and Care: Solvent extraction method

The simpler crack method allows the alkaloidal cocaine to precipitate without a solvent extraction method. Cocaine may then be smoked using various methods, such as a glass or regular pipe, or by mixing cocaine with tobacco or marijuana in cigarette form. This method of use is most irritating to the bronchial epithelium; bronchospasm may be a result of inflammation of the respiratory epithelium by either cocaine or adulterants. 

Solvent extraction

In a study comparing the acute effects of inhaled vs IV cocaine on airway dynam-ics, it was demonstrated that smoked cocaine base caused bronchoconstriction, whereas a similar intoxicating dose of IV cocaine did not. The most likely mechanism is because of a topical irritant effect of the cocaine or the contaminants with which it is mixed. IgE-mediated sensitivity to cocaine may also be a factor in some cases. 

Asthmatic patients who smoke cocaine may be at high risk for developing severe exacerbations of their asthma, depending on the degree of airways hyperresponsiveness, the dose of inhaled cocaine, and the nature of the contaminants inhaled during crack smoking.

The reported prevalence of cocaine use varies significantly because of selection and reporting biases. In the 1980s, Drug Abuse Warning Network data reflected an increase to 5.7 million regular cocaine users in the country by the end of the decade. Data from the 1997 National Household Survey on Drug Abuse estimates 1.5 million Americans aged > 12 years are regular cocaine users. 

However, the Office of National Drug Control Policy estimates the number of chronic cocaine users to be 3.6 million. About 40% of cocaine users use cocaine in the form of crack (National Household Survey on Drug Abuse data). It is the leading cause of illicit drug-related visits to EDs in the United States. In a prospective study by McNagny et al, the prevalence of cocaine use in young men presenting to an inner-city walk-in clinic was determined to be 39% by urine testing; 72% of those testing positive denied illicit drug use in the prior 3 days.

Canadian Health and Care Mall: Two alternative strategies merit study

Canadian Health and Care Mall:  Two alternative strategies merit study

Further understanding of the special needs and health-care barriers for this high utilization group is paramount to the success of the goals delineated in the Healthy People 2010 program. As demonstrated by Boudreaux and colleagues, race/ethnicity-based deficiencies persist as black and Hispanic asthma patients were more likely to utilize the ED and be admitted to the hospital. 

Health-care providers and policymakers must begin to understand why high-utilization patients report the ED as their usual source of asthma prescriptions and site for acute asthma care. Two alternative strategies merit study. First, patients with high NEDV warrant further investigation to delineate the challenges and barriers to high-quality care among health-disparate populations. 

Secondly, the impact of facilitated referral of ED asthma patients to asthma specialists while maintaining long-term overall patient management by the PCP should be investigated. The current data, in conjunction with prior studies, raise concerns about overreliance on “referral to PCP” as an effective response to the problems of this high-risk and expensive asthma population.

Limitations

This study has a few potential limitations. First, history of prior ED use was self-reported and there was no attempt to verify the accuracy of the stated information. It may be that subjects who reported six visits actually had more (or fewer) visits, but we believe the rank order to be accurate and believe that even one to two ED visits per year to be excessive. 

Another limitation is that we have not analyzed the outpatient management of these patients presenting with acute asthma; for example, we do not know how many received specialized asthma care in the past, and we are unable to evaluate how prior outpatient PCP management relates to the National Asthma Education and Prevention Program guidelines with Canadian Health and Care Mall. (watch website)

We have sparse data on compliance with prescribed medications, understanding of disease, and details of the written action plans (if present); these factors probably are associated with frequency of ED use and will require further study.

Canadian Health Care Management

 

Canadian Health Care Management

Health-care workers with OA from NRL have been able to safely return to work in settings where they avoid the personal use of NRL products, and where coworkers use powder-free, low-protein gloves. However, placing workers with toluene diisocyanate-induced asthma in environments with low-level exposures has not been as successful; overall, there is limited evidence for using this approach.

Continued exposure may lead to greater airway inflammation and potentially more airway remodeling and lower FEV₁. When patients are unwilling or unable to leave a job, the initiation of antiinflammatory and bronchodilator therapy may be the only management option available to the clinician, although the patient should be educated to understand that continued exposure may lead to a worse outcome; it is essential that patients have careful medical monitoring so that any worsening of asthma can be detected early and further interventions applied. Similarly, close monitoring is needed if patients continue to be exposed to a relevant work sensitizer while awaiting the outcome of a compensation claim.

Management

Limited data exist on the effect of the cessation of exposure in patients with irritant-induced OA.

One report of three patients with repetitive exposure to irritants at work suggested a benefit for removal from the exposure. 

Unlike workers with sensitizer-induced OA, however, workers with irritant-induced OA may be able to continue in their usual jobs if the risk of a similar high-level exposure to the inciting agent is diminished via engineering controls and similar means are employed to prevent subsequent WEA, including the appropriate use of respiratory protective devices. 

The rationale for this approach is based on the unproven assumption that irritant-induced airway inflammation in patients with irritant-induced OA will diminish with a reduction of exposure that is analogous to what may occur in patients with occupational or tobacco smoke-related chronic bronchitis with a reduction in exposure.

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Health&Care Mall: Constriction and relaxation venous capacitance

Health&Care Mall: Constriction and relaxation venous capacitance

The nose is lined by pseudostratified epithelium resting on a basement membrane, separating it from deeper submucosal layers. The submucosa contains mucous, seromucous, and serous glands.The small arteries, arterioles, and arteriovenous anastamoses determine regional blood flow. Capacitance vessels, consisting of veins and cavernous sinusoids, determine nasal patency. Constriction and relaxation of these venous capacitance vessels is regulated by the sympathetic nervous system. 

The cavernous sinusoids lie beneath the capillaries and venules, are most dense in the inferior and middle turbinates, and contain smooth-muscle cells controlled by the sympathetic nervous system. Loss of sympathetic tone or, to a lesser degree, cholinergic stimulation causes this sinusoidal erectile tissue to become engorged. Cholinergic stimulation causes arterial dilation and promotes the passive diffusion of plasma proteins into glands and the active secretion by mucous glands in cells.

Novel neurotransmitters, including substance P, calcitonin gene-related peptide, and vasointestinal peptide, have been detected in nasal secretions after nasal allergen challenge of patients with allergic rhinitis.Antidromic stimulation of sensory nerve fibers in the nose can release a variety of neurotrans-mitters including substance P, a mediator of increased vascular permeability. Because neurotrans-mitters also produce changes in regional blood flow and glandular secretion, their role in rhinitis may be important.

Nasal patency is predominantly controlled by changes in the capacitance vessels. Nasal airway resistance is responsible for approximately two thirds of the total airway resistance. Primary sites of nasal obstruction to airflow include the nasal vestibule, the nasal valves, and the nasal turbinates.

The nasal valve, the location of minimal cross-sectional area of the nares, contributes most to total nasal resistance. The entire nasal valve area resembles an inverted cone. It is bounded by the nasal septum medially, posterior end of the upper lateral cartilage, piriform aperture and the anterior head of the inferior turbinate posteriorly. 

This functional complex in Health&Care Mall pharmacy of compliant and dynamic tissues covers a distance of several millimeters. The valve lumen is regulated by lateral and medial erectile mucosa, modulated laterally by the tone of alar muscles, and stabilized by bone and cartilage. Septal erectile tissue, although not readily recognizable endoscopically, is clearly demonstrated by CT and histologically in cadaver studies.

Canada Health: Mode of action of reproductive toxicants

Reproductive toxicants can be divided into two categories based on their modes of action. Direct-acting toxicants Direct-acting toxic agents affect reproduction either through their chemical reactivity or by their structural similarity to an endogenous substance.

Chemically reactive toxicants damage important cellular components and tend to be non-specific, for example alkylating agents used in cancer chemotherapy. Lead, mercury and cadmium also probably act in this way. Structurally similar toxicants confuse the body into believing that they are biologically important compounds, for example hormones. Many are hormone agonists or  antagonists. 

The classical example here would be the combined contraceptive pill. It has been shown that occupational exposure to synthetic oestrogens and progestogens has led to infertility by suppression of gonadotrophin levels. Other toxicants with oestrogenic activity include PCB and PBB and organochlorine pesticides.

Toxicants acting indirectly

Indirect toxicants alter normal processes in one of two ways. They can be metabolised to a product that is more toxic than the parent compound or they can act by modifying naturally occurring enzymes or hormones. 

Enzymes present in Canadian Health Care Mall within the ovary and testis are responsible for the metabolic processing of many compounds that result in reproductive toxicity, for example cyclophosphamide, polycyclic aromatic hydrocarbons (PAH) and DBCR Other reproductive toxicants induce or inhibit enzymes in the gonads and liver that are involved in hormone metabolism. By interfering with hormone feedback pathways, normal reproductive control can be lost. Examples in this category include DDT, PCB and PBB.

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Canada Pharmacy: Relapse by Logistic Regression

Some authors have stated that most infections in AECB are noninvasive and will eventually resolve spontaneously. However, because the relapse rate from AECB is high (11 to 32%), better strategies for treatment of an acute exacerbation are needed. Authors currently recommend treatment of AECB with antibiotics if the patient presents with moderate to severe symptoms, but these authors state that patients with mild symptoms at presentation can be treated supportively.

Our data suggest that patients with documented COPD (even with mild symptoms at presentation) benefit from antibiotic therapy. However, the choice of antibiotic is important because the antibiotics were not all equally effective in lowering the risk of relapse.

One possibility for the high relapse rates of patients treated with amoxicillin is related to the increasing emergence of pathogen resistance. There are a significant number of reports of antimicrobial resistance among respiratory isolates common in patients with AECB (including Haemophilus influenzae, M catarrhalis, and S pneumoniae). This trend of increasing resistance has been reported across the United States, Canada, and Europe. Our institution (at the time of the study) had rates of resistance to amoxicillin of 30% for H influenzae isolates, 34% for S pneumoniae, and 32% for M catarrhalis.

The other antibiotics prescribed during the study period had resistance rates < 10%, with the exception of erythromycin (12% resistance for S pneumoniae) and trimethoprim/sulfamethoxazole (18% resistance for S pneumoniae). The elevated rates of resistance to amoxicillin suggest one possible explanation for the higher relapse rate observed in our patients who were treated with this medication.

Table 1 — Variables Identified as Risk Factors for Relapse by Logistic Regression

Variables	Wald x2 p Value	Coefficient	SE	Odds Ratio (95% Confidence Interval)
Amoxicillin	0.0056	1.22	0.44	3.37(1.44-8.13)
Any other antibiotic except amoxicillin	0.0001	-1.26	0.32	0.28 (0.15-0.53)
Coronary artery disease*	0.0002	1.72	0.46	5.60 (2.33-14.17)
Active smoking	0.0002	1.47	0.40	4.45 (2.09-10.13)

Health Mall: Regular tobacco smoking

Regular tobacco smoking has been associated with reduced Feno

Other studies in adolescents and adults have also reported increased Feno levels in men compared with women. However, in young children and infants, girls have raised Feno levels compared with boys, while there appears to be no gender difference for older children. The trend for increased Feno for girls compared with boys but men compared with women is in direct contrast to the natural history of asthma, which predominates in boys compared with girls but is higher in women compared with men. Our results suggest there is a maturational change in the relationship between Feno and gender. This could be due to relative changes in body mass or differences in NO synthase activity between genders.

tobacco smoking

Regular tobacco smoking has been associated with reduced Feno; however, the present analysis in Canadian Health Care Mall suggests that this relationship may only be evident for atopic individuals. The reasons for this are unknown but may result from increased susceptibility of the atopic airway epithelium to environmental irritants and consequent disruption of nitric oxide regulation.

Although this was an unselected population, there was a high prevalence of atopy among our subjects. This was unlikely to have influenced the outcomes for the analysis of atopic-only study subjects, but could have influenced the outcomes for nonatopic individuals where there were fewer individuals at risk for elevated Feno. Further, the adults in this study were the parents of the children we previously reported on. Similar findings may therefore be the result of shared genetic and environmental factors between children and parents. The relationship between Feno and other variables reported in the present study should therefore be tested elsewhere.

In summary, we have confirmed in adults our findings in children of an interaction of Feno with atopy and increased AR. Importantly, asthma was not directly related to levels of Feno once this interaction was accounted for. Meaningful interpretation of Feno may only be possible when atopy and increased AR are considered.

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