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Fragranced consumer products: effects on asthmatics

WAF Salutes Anne Steinemann, Department of Infrastructure Engineering, Melbourne School of Engineering, The University of Melbourne, Melbourne, VIC 3010 Australia

Fragranced consumer products, such as cleaning supplies, air fresheners, and personal care products, can emit a range of air pollutants and trigger adverse health effects. This study investigates the prevalence and types of effects of fragranced products on asthmatics in the American population. Using a nationally representative sample (n?=?1137), data were collected with an on-line survey of adults in the USA, of which 26.8% responded as being medically diagnosed with asthma or an asthma-like condition.

Results indicate that 64.3% of asthmatics report one or more types of adverse health effects from fragranced products, including respiratory problems (43.3%), migraine headaches (28.2%), and asthma attacks (27.9%). Overall, asthmatics were more likely to experience adverse health effects from fragranced products than non-asthmatics (prevalence odds ratio [POR] 5.76; 95% confidence interval [CI] 4.34–7.64). In particular, 41.0% of asthmatics report health problems from air fresheners or deodorizers, 28.9% from scented laundry products coming from a dryer vent, 42.3% from being in a room cleaned with scented products, and 46.2% from being near someone wearing a fragranced product. Of these effects, 62.8% would be considered disabling under the definition of the Americans with Disabilities Act. Yet 99.3% of asthmatics are exposed to fragranced products at least once a week. Also, 36.7% cannot use a public restroom if it has an air freshener or deodorizer, and 39.7% would enter a business but then leave as quickly as possible due to air fresheners or some fragranced product. Further, 35.4% of asthmatics have lost workdays or a job, in the past year, due to fragranced product exposure in the workplace. More than twice as many asthmatics would prefer that workplaces, health care facilities and health care professionals, hotels, and airplanes were fragrance-free rather than fragranced. Results from this study point to relatively simple and cost-effective ways to reduce exposure to air pollutants and health risks for asthmatics by reducing their exposure to fragranced products.

The online version of this article (10.1007/s11869-017-0536-2) contains supplementary material, which is available to authorized users.
Keywords: Asthma, Fragranced consumer products, Indoor air quality, Fragrance, Health effects, Volatile organic compounds, Semi-volatile organic compounds

Introduction

Fragranced consumer products pervade society and emit numerous volatile organic compounds, such as limonene, alpha-pinene, beta-pinene, acetaldehyde, and formaldehyde (Steinemann 2015; Nazaroff and Weschler 2004), and semi-volatile organic compounds, such as musks and phthalates (Weschler 2009; Just et al. 2010). However, ingredients in fragranced products are exempt from full disclosure on product labels or safety data sheets (Steinemann 2015), limiting awareness of potential emissions and exposures. Fragranced products have been associated with a range of adverse health effects including work-related asthma (Weinberg et al. 2017), asthmatic exacerbations (Kumar et al. 1995; Millqvist and Löwhagen 1996), respiratory difficulties (Caress and Steinemann 2009), mucosal symptoms (Elberling et al. 2005), migraine headaches (Kelman 2004), and contact dermatitis (Rastogi et al. 2007; Johansen 2003), as well as neurological, cardiovascular, cognitive, musculoskeletal, and immune system problems (Steinemann 2016).

This article investigates specifically the effects of exposure to fragranced products on asthmatics in the US population. In addition to health impacts, it also investigates societal access, preferences for fragrance-free environments, awareness of fragranced product emissions, and implications for air quality and health. It compares results from the sub-population of asthmatics with non-asthmatics, as well as with the general US population, as reported in Steinemann (2016). The study provides important data on the extent and severity of the problem, pointing to opportunities to reduce the adverse health, economic, and societal effects by reducing exposure to fragranced products.

Methods

A nationally representative on-line survey was conducted of the US population, representative of age, gender, and region (n?=?1137, confidence limit?=?95%, confidence interval?=?3%). The survey drew upon a large web-based US panel (over 5,000,000 people) held by Survey Sampling International, using randomized participant recruitment (SSI 2016). The survey instrument was developed and tested over a two-year period before full implementation in June 2016. The survey response rate was 95% (responses to panel recruitment 1201; screen-outs 13; drop-outs 46; completes 1137), and all responses were anonymous. The research study received ethics approval from the University of Melbourne. Details on the survey methodology are provided as a supplemental document.

This article extends and deepens the general population study of Steinemann (2016) by analyzing specifically the effects on asthmatics and compared to non-asthmatics and the general population. Of the general population surveyed, 26.8% responded as being medically diagnosed with either asthma (15.2%, n?=?173) or an asthma-like condition (12.5%, n?=?142) or both (26.8%, n?=?305). For the purposes of the article, the sub-population of “asthmatics” will be those medically diagnosed with asthma, an asthma-like condition, or both; the sub-population of “non-asthmatics” will be those in the general population other than asthmatics.

Survey questions investigated use and exposure to fragranced products, both from one’s own use and from others’ use, exposure contexts and products, health effects related to exposures, impacts of fragrance exposure in the workplace and in society, awareness of fragranced product ingredients and labeling, preferences for fragrance-free environments and policies, and demographic information.

Specific exposure contexts included air fresheners or deodorizers used in public restrooms and other environments, scented laundry products coming from a dryer vent, being in a room after it was cleaned with scented cleaning products, being near someone wearing a fragranced product, entering a business with the scent of fragranced products, fragranced soap used in public restrooms, and ability to access environments that used fragranced products.

Fragranced products were categorized as follows: (a) air fresheners and deodorizers (e.g., sprays, solids, oils, disks); (b) personal care products (e.g., soaps, hand sanitizer, lotions, deodorant, sunscreen, shampoos); (c) cleaning supplies (e.g., all-purpose cleaners, disinfectants, dishwashing soap); (d) laundry products (e.g., detergents, fabric softeners, dryer sheets); (e) household products (e.g., scented candles, restroom paper, trash bags, baby products); (f) fragrance (e.g., perfume, cologne, after-shave); and (g) other.

Health effects were categorized as follows: (a) migraine headaches; (b) asthma attacks; (c) neurological problems (e.g., dizziness, seizures, head pain, fainting, loss of coordination); (d) respiratory problems (e.g., difficulty breathing, coughing, shortness of breath); (e) skin problems (e.g., rashes, hives, red skin, tingling skin, dermatitis); (f) cognitive problems (e.g., difficulties thinking, concentrating, or remembering); (g) mucosal symptoms (e.g., watery or red eyes, nasal congestion, sneezing); (h) immune system problems (e.g., swollen lymph glands, fever, fatigue); (i) gastrointestinal problems (e.g., nausea, bloating, cramping, diarrhea); (j) cardiovascular problems (e.g., fast or irregular heartbeat, jitteriness, chest discomfort); (k) musculoskeletal problems (e.g., muscle or joint pain, cramps, weakness); and (j) other. Categories were derived from prior studies of fragranced products and health effects (Caress and Steinemann 2009; Miller and Prihoda 1999) and pre-tested before full survey implementation.

Results

Main findings are presented in this section, and full results for asthmatics, non-asthmatics, and the general population are provided as supplemental documentation. Demographic information is provided in Table ?Table11.

Table 1

Demographic information
Asthmatics Non-asthmatics General population
N N N
% of column total N
% of general population row N
% of column total
% of column total % of general population row
Total 305 305 832 832 1137
100.0% 26.8% 100.0% 73.2% 100.0%
Male/female
?All males 136 136 389 389 525
44.6% 25.9% 46.8% 74.1% 46.2%
?All females 169 169 443 443 612
55.4% 27.6% 53.2% 72.4% 53.8%
Gender–age
?Male 18–24 16 16 31 31 47
5.2% 34.0% 3.7% 66.0% 4.1%
?Male 25–34 36 36 94 94 130
11.8% 27.7% 11.3% 72.3% 11.4%
?Male 35–44 42 42 94 94 136
13.8% 30.9% 11.3% 69.1% 12.0%
?Male 45–54 30 30 78 78 108
9.8% 27.8% 9.4% 72.2% 9.5%
?Male 55–65 12 12 92 92 104
3.9% 11.5% 11.1% 88.5% 9.1%
?Female 18–24 26 26 52 52 78
8.5% 33.3% 6.3% 66.7% 6.9%
?Female 25–34 40 40 95 95 135
13.1% 29.6% 11.4% 70.4% 11.9%
?Female 35–44 43 43 112 112 155
14.1% 27.7% 13.5% 72.3% 13.6%
?Female 45–54 41 41 103 103 144
13.4% 28.5% 12.4% 71.5% 12.7%
?Female 55–65 19 19 81 81 100
6.2% 19.0% 9.7% 81.0% 8.8%
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Fragranced product exposure

Among asthmatics, 99.0% are exposed to fragranced products at least once a week, from their own use (71.1% air fresheners and deodorizers; 85.9% personal care products; 78.4% cleaning supplies; 81.3% laundry products; 76.7% household products; 67.5% fragrance; 3.6% other). Further, 94.8% are exposed to fragranced products at least once a week, from others’ use. Combined, 99.3% of asthmatics are exposed to fragranced products through their own use, others’ use, or both. Among non-asthmatics, 98.1% are exposed to fragranced products at least once a week from their own use, 91.1% from others’ use, and 98.9% from either or both. Thus, asthmatics are more likely to be exposed to fragranced products, from their own use and others’ use and both, than non-asthmatics (POR, 1.66; 95% CI, 0.36–7.71).
Adverse health effects

Among asthmatics, 64.3% reported one or more types of adverse health effects from exposure to one or more types of fragranced products (43.3% respiratory problems; 27.2% mucosal symptoms; 28.2% migraine headaches; 19.0% skin problems; 27.9% asthma attacks; 15.1% neurological problems; 14.1% cognitive problems; 12.1% gastrointestinal problems; 9.8% cardiovascular problems; 11.1% immune system problems; 9.5% musculoskeletal problems; and 1.3% other). Among non-asthmatics, 23.8% reported one or more types of adverse health effects from exposure to one or more types of fragranced products (see Table ?Table2).2). Thus, among all types of health effects (excepting asthma attacks), asthmatics are more likely to be affected than non-asthmatics (POR 5.76; 95% CI, 4.34–7.64).
Table 2

Frequency and types of adverse health effects reported from exposure to fragranced consumer products
Asthmatics Non-asthmatics General population
305 832 1137
26.8% 73.2% 100.0%
Migraine headaches 86 93 179
28.2% 11.2% 15.7%
Asthma attacks 85 6 91
27.9% 0.7% 8.0%
Neurological problems 46 36 82
15.1% 4.3% 7.2%
Respiratory problems 132 79 211
43.3% 9.5% 18.6%
Skin problems 58 63 121
19.0% 7.6% 10.6%
Cognitive problems 43 23 66
14.1% 2.8% 5.8%
Mucosal symptoms 83 101 184
27.2% 12.1% 16.2%
Immune system problems 34 11 45
11.1% 1.3% 4.0%
Gastrointestinal problems 37 26 63
12.1% 3.1% 5.5%
Cardiovascular problems 30 20 50
9.8% 2.4% 4.4%
Musculoskeletal problems 29 14 43
9.5% 1.7% 3.8%
Other 4 15 19
1.3% 1.8% 1.7%
Total 196 198 394
(One or more health problems) 64.3% 23.8% 34.7%
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Of the 64.3% of asthmatics reporting adverse health effects from fragranced products, proportionately more males report adverse effects than females, relative to non-asthmatics (asthmatic 52.0% female, 48.0% male; non-asthmatic 60.1% female, 39.9% male) (POR 1.39; 95% CI, 0.93–2.97) (see Table ?Table3).3). Among all age groups, proportionately more asthmatics in age group 25–34 report adverse effects relative to non-asthmatics (asthmatic 69.7%; non-asthmatic 23.3%) (POR 7.59; 95% CI, 4.19–13.76). Among all gender and age groups, proportionately more males age 25–34 report adverse effects relative to non-asthmatics (asthmatic 83.3%; non-asthmatic 18.1%) (POR 22.65; 95% CI, 8.15–62.92).
Table 3

Demographic information for individuals reporting adverse effects from exposure to fragranced products
Asthmatics Non-asthmatics General population
N
% of column total N
% of asthmatics row, Table ?Table11 N
% of column total N
% of non-asthmatics row, Table ?Table11 N
% of column total N
% of general population row, Table 1
Total 196 196 198 198 394 394
100.0% 64.3% 100.0% 23.8% 100.0% 34.7%
Male/female
?All males 94 94 79 79 173 173
48.0% 69.1% 39.9% 20.3% 43.9% 33.0%
?All females 102 102 119 119 221 221
52.0% 60.4% 60.1% 26.9% 56.1% 36.1%
Gender–age
?Male 18–24 8 8 6 6 14 14
4.1% 50.0% 3.0% 19.4% 3.6% 29.8%
?Male 25–34 30 30 17 17 47 47
15.3% 83.3% 8.6% 18.1% 11.9% 36.2%
?Male 35–44 31 31 24 24 55 55
15.8% 73.8% 12.1% 25.5% 14.0% 40.4%
?Male 45–54 17 17 15 15 32 32
8.7% 56.7% 7.6% 19.2% 8.1% 29.6%
?Male 55–65 8 8 17 17 25 25
4.1% 66.7% 8.6% 18.5% 6.3% 24.0%
?Female 18–24 12 12 8 8 20 20
6.1% 46.2% 4.0% 15.4% 5.1% 25.6%
?Female 25–34 23 23 27 27 50 50
11.7% 57.5% 13.6% 28.4% 12.7% 37.0%
?Female 35–44 28 28 33 33 61 61
14.3% 65.1% 16.7% 29.5% 15.5% 39.4%
?Female 45–54 27 27 26 26 53 53
13.8% 65.9% 13.1% 25.2% 13.5% 36.8%
?Female 55–65 12 12 25 25 37 37
6.1% 63.2% 12.6% 30.9% 9.4% 37.0%
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Specific exposure contexts

Air fresheners and deodorizers were associated with health problems for 41.0% of asthmatics (54.4% respiratory problems, 39.2% asthma attacks, 29.6% mucosal symptoms, 36.8% migraine headaches, 15.2% neurological problems, 26.4% skin problems, and others), and for 12.9% of non-asthmatics (see Table ?Table4).4). Thus, asthmatics were more likely to experience adverse effects from air fresheners than non-asthmatics (POR 4.71; 95% CI, 3.47–6.39).
Table 4

Frequency and types of health problems experienced by asthmatics, non-asthmatics, and the general population from exposure to four types of fragranced consumer products
Air fresheners or deodorizers Scented laundry products Scented cleaning products Fragranced person
Asth Non-asth Gen Pop Asth Non-asth Gen Pop Asth Non-asth Gen Pop Asth Non-asth Gen Pop
Health problem 125 107 232 88 54 142 129 95 224 141 127 268
41.0% 12.9% 20.4% 28.9% 6.5% 12.5% 42.3% 11.4% 19.7% 46.2% 15.3% 23.6%
Migraines 46 36 82 24 13 37 42 33 75 45 51 96
36.8% 33.6% 35.3% 27.3% 24.1% 26.1% 32.6% 34.7% 33.5% 31.9% 40.2% 35.8%
Asthma attacks 49 4 53 27 1 28 42 4 46 41 3 44
39.2% 3.7% 22.8% 30.7% 1.9% 19.7% 32.6% 4.2% 20.5% 29.1% 2.4% 16.4%
Neurological 19 17 36 16 8 24 28 19 47 27 14 41
15.2% 15.9% 15.5% 18.2% 14.8% 16.9% 21.7% 20.0% 21.0% 19.1% 11.0% 15.3%
Respiratory 68 40 108 34 12 46 67 42 109 77 41 118
54.4% 37.4% 46.6% 38.6% 22.2% 32.4% 51.9% 44.2% 48.7% 54.6% 32.3% 44.0%
Skin 33 32 65 22 19 41 25 20 45 24 15 39
26.4% 29.9% 28.0% 25.0% 35.2% 28.9% 19.4% 21.1% 20.1% 17.0% 11.8% 14.6%
Cognitive 15 16 31 9 6 15 21 10 31 21 9 30
12.0% 15.0% 13.4% 10.2% 11.1% 10.6% 16.3% 10.5% 13.8% 14.9% 7.1% 11.2%
Mucosal 37 49 86 27 21 48 35 48 83 40 58 98
29.6% 45.8% 37.1% 30.7% 38.9% 33.8% 27.1% 50.5% 37.1% 28.4% 45.7% 36.6%
Immune system 16 5 21 16 3 19 18 5 23 17 2 19
12.8% 4.7% 9.1% 18.2% 5.6% 13.4% 14.0% 5.3% 10.3% 12.1% 1.6% 7.1%
Gastrointestinal 18 13 31 20 9 29 17 15 32 21 10 31
14.4% 12.1% 13.4% 22.7% 16.7% 20.4% 13.2% 15.8% 14.3% 14.9% 7.9% 11.6%
Cardiovascular 18 12 30 11 4 15 16 10 26 15 5 20
14.4% 11.2% 12.9% 12.5% 7.4% 10.6% 12.4% 10.5% 11.6% 10.6% 3.9% 7.5%
Musculoskeletal 19 8 27 21 2 23 13 10 23 15 2 17
15.2% 7.5% 11.6% 23.9% 3.7% 16.2% 10.1% 10.5% 10.3% 10.6% 1.6% 6.3%
Other 2 6 8 1 3 4 2 2 4 2 5 7
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Scented laundry products coming from a dryer vent were associated with health problems for 28.9% of asthmatics (38.6% respiratory problems, 30.7% asthma attacks, 30.7% mucosal symptoms, 27.3% migraine headaches, 18.2% neurological problems, 25.0% skin problems, and others), and for 6.5% of non-asthmatics (see Table ?Table4).4). Thus, asthmatics were more likely to experience adverse effects from scented laundry products coming from a dryer vent than non-asthmatics (POR 5.84; 95% CI, 4.03–8.46).

Being in a room after it has been cleaned with scented products was associated with health problems for 42.3% of asthmatics (51.9% respiratory problems, 32.6% asthma attacks, 27.1% mucosal symptoms, 32.6% migraine headaches, 21.7% neurological problems, 19.4% skin problems, and others), and for 11.4% of non-asthmatics (see Table ?Table4).4). Thus, asthmatics were more likely to experience adverse effects from being in a room after it has been cleaned with scented products than non-asthmatics (POR 5.69; 95% CI, 4.16–7.77).

Being near someone wearing a fragranced product was associated with health problems for 46.2% of asthmatics (54.6% respiratory problems, 29.1% asthma attacks, 28.4% mucosal symptoms, 31.9% migraine headaches, 19.1% neurological problems, 17.0% skin problems, and others), and 15.3% of non-asthmatics (see Table ?Table4).4). Thus, asthmatics were more likely to experience adverse effects from being near someone wearing a fragranced product than non-asthmatics (POR 4.77; 95% CI, 3.56–6.40).

Exposure to fragranced products can trigger disabling health effects, according to criteria from the Americans with Disabilities Act (ADA 1990): “Do any of these health problems substantially limit one or more major life activities, such as seeing, hearing, eating, sleeping, walking, standing, lifting, bending, speaking, breathing, learning, reading, concentrating, thinking, communicating, or working, for you personally?” Among asthmatics reporting health problems, 62.8% reported that the severity of the health effect from fragranced product exposure was potentially disabling. Thus, asthmatics were more likely to report disabling health effects from fragranced products than non-asthmatics (POR 7.13; 95% CI, 5.11–9.95).
Ingredient disclosure and product claims

Among asthmatics, 41.3% were not aware that a “fragrance” in a product is typically a chemical mixture of several dozen to several hundred chemicals, 57.4% were not aware that fragrance chemicals do not need to be fully disclosed on the product label or material safety data sheet, and 58.0% were not aware that fragranced products typically emit hazardous air pollutants such as formaldehyde. Further, 64.3% of asthmatics, and 75.7% of non-asthmatics, were not aware that even so-called natural, green, and organic fragranced products typically emit hazardous air pollutants (28.9% of asthmatics and 15.7% of non-asthmatics were aware). However, 60.3% of asthmatics, and 60.1% of non-asthmatics, would not still use a fragranced product if they knew it emitted hazardous air pollutants.
Societal and workplace effects

Fragranced products can also present barriers for asthmatics in public places and the workplace. Among asthmatics, 36.7% are prevented from using the restrooms in a public place, because of the presence of an air freshener, deodorizer, or scented product. Also, 28.9% are prevented from washing their hands with soap in a public place, if the soap is fragranced. Further, 43.9% are prevented from going to some place because they would be exposed to a fragranced product that would make them sick. Notably, 39.7% report that if they enter a business, and smell air fresheners or some fragranced product, they want to leave as quickly as possible.

Significantly, 35.4% of asthmatics, and 7.7% of non-asthmatics, have become sick, lost workdays, or lost a job, in the past 12 months, due to fragranced products in their work environment. Thus, asthmatics were more likely to have lost workdays or lost a job due to illness from fragranced products in their work environment than non-asthmatics (POR 6.58; 95% CI, 4.65–9.30).

Fragrance-free policies receive a strong majority of support. Among asthmatics, 66.2% would be supportive of a fragrance-free policy in the workplace (compared to 16.1% that would not). Thus, more than four times as many asthmatics would prefer a fragrance-free workplace than fragranced. Also, 72.1% of asthmatics would prefer that health care facilities and health care professionals be fragrance-free (compared to 14.8% that would not). Thus, nearly five times as many asthmatics would prefer fragrance-free health care facilities and professionals than fragranced.

Among non-asthmatics, 48.3% would support a fragrance-free workplace (compared with 21.0% that would not), and among the general population, 53.1% would support a fragrance-free workplace (compared with 19.7% that would not). Thus, regardless of population, fragrance-free workplaces receive more than twice as many in support as not.

Asthmatics also strongly prefer fragrance-free airplanes and hotels. If given a choice between flying on an airplane that pumped scented air throughout the passenger cabin, or did not pump scented air throughout the passenger cabin, 63.6% of asthmatics would choose an airplane without scented air (compared to 24.9% with scented air). Similarly, if given a choice between staying in a hotel with fragranced air, or without fragranced air, 63.0% would choose a hotel without fragranced air (compared to 28.5% with fragranced air).

Among non-asthmatics, 57.6 and 52.9% would prefer fragrance-free airplanes and hotels, respectively (compared with 23.1 and 27.5% that would not) and among the general population, 59.2 and 55.6% would prefer fragrance-free airplanes and hotels, respectively (compared with 23.6 and 27.8% that would not). Thus, overall, more than twice as many asthmatics, as well as the general population, would prefer that airplanes and hotels were fragrance-free rather than fragranced.

Discussion

Asthma is a serious and increasing health condition, affecting an estimated 25 million Americans, and costing an estimated $56 billion annually in medical expenses, missed school and work days, and premature deaths (CDCP 2017a). Nearly 12 million Americans had an asthma attack in 2015, many of which could have been prevented (CDCP 2017b).

Results from this study show that asthmatics are profoundly, adversely, and disproportionately affected by exposure to fragranced consumer products. While non-asthmatics are also affected, asthmatics are more likely to experience adverse health effects from exposure (POR 5.76; 95% CI 4.34–7.64).

Of particular concern are involuntary exposures to fragranced products, such as in health care facilities and workplaces. Asthmatics are prevented from accessing public toilets, businesses, and workplaces due to adverse health effects from fragranced products. Further, 35.4% have lost workdays or a job, in the past year, due to fragranced product exposure in the workplace. More than twice as many asthmatics would prefer that workplaces, health care facilities, health care professionals, airplanes, and hotels were fragrance-free than fragranced.

Limitations of the study include the following: (a) data were based on self-reports, although a well-established method for survey research; (b) all possible products and health effects were not included, although the low percentages for responses in the “other” category indicates the survey captured the primary products and effects; (c) product emissions and exposures were not measured directly; (d) the cross-sectional design of the study, while useful for determining prevalence, provides data that represent just one point in time, limiting the analysis of risk factors, temporal relationships between exposures and effects, and trends in prevalence, and (e) only adults (ages 18–65) were included in the survey, which overlooks the effects of fragranced products on children (such as in day care facilities and schools) and on seniors (such as in retirement communities and assisted living facilities).

Results of this study provide strong evidence that fragranced consumer products can harm health for both asthmatics and non-asthmatics, with asthmatics more affected. Understanding why these products are associated with a range of health problems is a critical topic that requires further research. Fragranced products emit a range of volatile and semi-volatile organic compounds, some of which are associated with adverse health effects, but virtually none of which need to be disclosed (Steinemann 2009, 2015), thus limiting scientific inquiry and public awareness of potential exposures to problematic compounds. A broader mechanistic framework is needed to understand which ingredients, or combinations of ingredients, could be associated with the adverse health outcomes reported in this study. In the meantime, a prudent and practical approach, and one that would provide direct and immediate benefits, would be to limit exposure to fragranced consumer products.

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Perfumes, Magazines and Severe Asthma

Perfumes Strips and Scents in Magazines “Negatively Affect Asthmatics and adverse respiratory reactions to perfumes says study. In honor of #AsthmaAwarenessWeek and #WorldAsthmaDay can we stop doing this?

Note from the World Asthma Foundation. This study dates back to 1994. How much education is needed to change behavior? Can we PLEASE stop this practice already? It’s 2020 and we all know this to be true already right? Just saying People @people magazine.

Background

Perfume- and cologne-scented advertisement strips are widely used. There are, however, very few data on the adverse effects of perfume inhalation in asthmatic subjects.

OBJECTIVES:

This study was undertaken to determine whether perfume inhalation from magazine scent strips could exacerbate asthma.

METHODS:

Twenty-nine asthmatic adults and 13 normal subjects were included in the study. Histories were obtained and physical examinations performed. Asthma severity was determined by clinical criteria of the U.S.National Heart, Lung, and Blood Institute (NHLBI). Skin prick tests with common inhalant allergens and with the perfume under investigation were also performed. Four bronchial inhalation challenges were performed on each subject using commercial perfume scented strips, filter paper impregnated with perfume identical to that of the commercial strips, 70% isopropyl alcohol, and normal saline, respectively. Symptoms and signs were recorded before and after challenges. Pulmonary function studies were performed before and at 10, 20, and 30 minutes after challenges.
RESULTS:

Inhalational challenges using perfume produced significant declines in FEV1 in asthmatic patients when compared with control subjects. No significant change in FEV1 was noted after saline (placebo) challenge in asthmatic patients. The percent decline in FEV1 was significantly greater after challenge in severely asthmatic patients as compared with those with mild asthma. Chest tightness and wheezing occurred in 20.7% of asthmatic patients after perfume challenges. Asthmatic exacerbations after perfume challenge occurred in 36%, 17%, and 8% of patients with severe, moderate, and mild asthma, respectively. Patients with atopic asthma had greater decreases in FEV1 after perfume challenge when compared with patients with nonallergic asthma.

CONCLUSIONS:

Perfume-scented strips in magazines can cause exacerbations of symptoms and airway obstruction in asthmatic patients. Severe and atopic asthma increases risk of adverse respiratory reactions to perfumes.

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U.S National Institutes of Health stands with Asthma patients, families, advocates, researchers, and health care professionals

Today on @WorldAsthmaDay, the U.S National Institutes of Health stands with patients, families, advocates, researchers, and health care professionals to raise awareness about this common chronic respiratory disease, the people it affects, and the biomedical research that improves its prevention and treatment.

Asthma is a chronic lung disease that causes periods of wheezing, chest tightness, shortness of breath, and coughing. It is a major contributing factor to missed time from school and work, with severe attacks requiring emergency room visits and hospitalizations. Sometimes these asthma attacks can be fatal.

This year, we recognize that the coronavirus disease 2019 (COVID-19) pandemic is creating concern and uncertainty for many people around the globe, including those with asthma. The disease can affect the nose, throat, and lungs, cause an asthma attack, and possibly lead to pneumonia and acute respiratory disease. According to the Centers for Disease Control and Prevention(link is external), people with asthma should continue their current asthma medications and discuss any concerns with their healthcare provider. Researchers at NIH and elsewhere are working to learn more about COVID-19 and to develop specific treatments and vaccines.

Three NIH institutes support and conduct studies on asthma — the National Institute of Environmental Health Sciences (NIEHS); the National Heart, Lung, and Blood Institute (NHLBI); and the National Institute of Allergy and Infectious Diseases (NIAID). Institute scientists and grantees made several important advances in understanding, treating, and managing asthma in 2019. These findings and other highlights are featured in five topic areas below:

Relationship between asthma and COVID-19
Populations at risk of developing asthma
Potential new treatments
Genes involved in asthma
Asthma management

Relationship between asthma and COVID-19

NIAID is initiating a home-based study to assess the incidence of infection with SARS-CoV-2, the virus that causes COVID-19, in children and their caregivers and siblings. A key objective of this observational study will be to determine if infection rates or immune responses to SARS-CoV-2 infection differ in children who have asthma or other allergic conditions compared to those who have not been diagnosed with or treated for these conditions.

NIAID also is starting an observational study in patients hospitalized for COVID-19 to understand if specific characteristics of the immune response influence or reflect the severity of infection. This study may help determine whether underlying diseases, such as asthma, influence the body’s response to SARS-CoV-2 infection.
Populations at risk of developing asthma

Children

NIH scientists are making progress in understanding the underlying factors that contribute to the development of asthma in U.S. children. This year, an international collaboration led by NIEHS scientists reported that the presence of newly discovered novel epigenetic markers — or chemical tags that attach to DNA — may indicate a newborn’s risk of developing asthma. The data were generated by the Pregnancy and Childhood Epigenetics Consortium and may help researchers find asthma biomarkers, or molecular indicators of asthma, and identify at birth which children will eventually develop the condition.

At NHLBI, researchers discovered a link(link is external) between childhood asthma flare ups and changes in the lung microbiome, the communities of bacteria and other microorganisms that are normally present in the lung and usually do not cause symptoms. The scientists determined that children with mild to moderate asthma who experienced early signs of an upcoming asthma flare up tended to have higher levels of certain types of disease-causing bacteria in their lungs. The study could lead to a precision medicine approach for treating mild to moderate childhood asthma by altering the number and types of bacteria in a child’s airways.

Ongoing NIAID-funded clinical studies focus on interventions to prevent asthma development in children at high risk of developing the condition. One team of researchers studied a large group of children who were hospitalized as infants with bronchiolitis, a common early-life lung infection usually caused by a virus. The scientists found that recurrent wheezing by age 3 is at least three times more likely to occur in children whose bronchiolitis was associated with a rhinovirus C infection and who also had early signs of allergy to foods or inhaled allergens.

African Americans and people of African ancestry

Another group that bears a disproportionate burden of asthma is African Americans. In an NHLBI-funded study that is the largest genome-wide association study of asthma in African ancestry populations to date, researchers identified two novel regions on a specific chromosome that may be linked to asthma risk. The scientists theorize that a better understanding of the genetic risk factors for asthma in African ancestry populations will lead to development of better therapeutic interventions.
Potential new treatments

Using a mouse model of asthma, NIEHS researchers reported a possible treatment for neutrophilic asthma, a particularly severe form that responds poorly to the standard asthma therapy of corticosteroids. The orally available drug VTP-938 made it easier for the mice to breathe after they were exposed to house dust extracts. The results suggest that VTP-938 may be an innovative treatment for humans with this steroid-resistant form of asthma.
Genes involved in asthma

An NIAID-funded study sought to understand why some, but not all, colds lead to asthma attacks among children with asthma. The scientists obtained nasal washings from 106 children with severe asthma who experienced cold symptoms. Members of the research team compared samples from those who required corticosteroids after a cold-induced asthma attack and those who did not have an asthma attack following a cold. The research team found that colds that led to an asthma attack caused changes in the production of six families of genes that are associated with maintaining the function of the outermost layer of tissue lining the respiratory tract and with the responses of immune cells in close contact with this layer.

Variations in two genes — the aryl hydrocarbon receptor nuclear translocator (ARNT) and the protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) — are associated with immune-mediated diseases, such as asthma, in several ethnicities, according to NIEHS researchers and their collaborators. Because ARNT and PTPN22 are sensitive to environmental factors, this study is the first to demonstrate across ethnicities the combined role of these genes and environmental changes in the development of immune-related conditions like asthma.
Asthma management

NHLBI’s National Asthma Education Prevention Program is coordinating the 2020 focused updates to the 2007 Asthma Management Guidelines. These guidelines are designed to improve the care of people living with asthma as well as help primary care providers and specialists make decisions about asthma management. NHLBI released the updated focus areas of the guidelines for public comment, and the final recommendations for these areas are expected to be published later this year. They will address several priority topic areas listed below:

Using inhaled medications when needed
A new type of inhaled medication called long acting muscarinic antagonists
Treating allergies by exposure to low doses of allergens by mouth or with shots
Reducing indoor asthma triggers
A new procedure for asthma known as bronchial thermoplasty
A fractional exhaled nitric oxide test that may be helpful in diagnosing or managing asthma

Experts hope that these guidelines will help reduce the burden of asthma nationwide and improve the quality of life for those living with the condition.

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Difficult Asthma and Fungus

 

If you or someone you know suffers from Severe Asthma, then it will be worth your time to learn about the world of Asthma and Fungi. While this paper is pretty technical and lengthy by design, it will provide you with a glimpse of how fungi and asthma are linked.

The World Asthma Foundation (WAF) salutes the Department of Paediatric Respiratory Medicine, Royal Brompton Hospital Harefield NHS Foundation and Paediatric Respiratory Medicine, National Heart and Lung Institute, Imperial College, Sydney Street for their contribution to medicine and those that suffer from Asthma. The WAF will cover this topic in more depth in future post.

Fungi have many potential roles in paediatric asthma, predominantly by being a source of allergens (severe asthma with fungal sensitization, SAFS), and also directly damaging the epithelial barrier and underlying tissue by releasing proteolytic enzymes (fungal bronchitis). The umbrella term ‘fungal asthma‘ is proposed for these manifestations. Allergic bronchopulmonary aspergillosis (ABPA) is not a feature of childhood asthma, for unclear reasons. Diagnostic criteria for SAFS are based on sensitivity to fungal allergen(s) demonstrated either by skin prick test or
specific IgE. In children, there are no exclusion criteria on total IgE levels or IgG precipitins because of the rarity of ABPA. Diagnostic criteria for fungal bronchitis are much less well established. Data in adults and children suggest SAFS is associated with worse asthma control and greater susceptibility to asthma attacks than non-sensitized patients. The data on whether antifungal therapy is beneficial are conflicting. The pathophysiology of SAFS is unclear, but the epithelial alarmin interleukin-33 is implicated. However, whether individual fungi have different pathobiologies is unclear. There are many unanswered questions needing further research, including how fungi interact with other allergens, bacteria, and viruses, and what optimal therapyshould be, including whether anti-neutrophilic strategies, such as macrolides, should be used.

Considerable further research is needed to unravel the complex roles of different fungi in severe asthma.

  1. Introduction
    The important role of fungi in worsening asthma has long been appreciated. In 2006, the term
    ‘severe asthma with fungal sensitization (SAFS)’ was first proposed in a review article that rightly
    acknowledged the historical evidence implicating fungi in the pathophysiology of asthma going
    back to the seventeenth century [1]. The role of fungi in asthma remains controversial to the present
    day, and these issues are reviewed below. What is certainly beyond dispute is that (a) although
    most acute attacks of asthma are precipitated by a viral infection, a sudden heavy aeroallergen load,
    such as grass pollen (“thunderstorm asthma”) [2] or soya bean (ships unloading in the docks of
    Barcelona) [3], can precipitate severe attacks, which might be eosinophilic rather than neutrophilic
    [4]; and, (b) fungal allergens can also cause acute attacks of asthma [5–7].
    The term SAFS focuses on allergic sensitization, but this is quite restrictive, because allergy is
    not the only mechanism whereby fungi can modulate asthma. Additional to allergic sensitization,
    which does not necessarily require airway fungal infection, is the release of tissue damaging
    proteases and other enzymes, which might disrupt the airway epithelial barrier and cause mucosal
    damage and airway remodeling [8]. For this to happen, a chronic fungal bronchitis needs to be
    J. Fungi 2019, 6, 55 2 of 17
    established. Sensitization and tissue damage both may co-exist. Here, I propose that the more
    general term ‘fungal asthma’ is used to encompass allergic sensitization (SAFS), fungal bronchitis,
    and combined sensitization/bronchitis (Figure 1). In adults, this would also include ABPA, not
    discussed here because of the rarity of this condition in children with asthma. All three entities may
    potentially benefit from anti-fungals, but fungal bronchitis without sensitization should not require
    the intensification of anti-Type 2 inflammatory medications. Of course, the pro-inflammatory
    effects of tissue damaging enzymes may merit treatment (as, for example, the anti-inflammatory
    strategies that may be used in cystic fibrosis (CF) [9,10] to counter the effects of infection driven,
    neutrophilic tissue destruction. The picture might also be dynamic; increasing inhaled steroids may
    cause topical immunosuppression (discussed in more detail below) and, thus, predispose to fungal
    bronchitis as a secondary phenomenon.
    Figure 1. Schematic of fungal involvement in asthma in children, in whom the diagnosis of allergic
    bronchopulmonary aspergillosis (ABPA) is rarely made.
    The justification for this sort of phenotyping is that it is clinically useful, because defining it
    leads to a change in management. Unfortunately, much of the paediatric guidance has had to be
    extrapolated from work in adults. The aim of this review is to assess the clinical utility of current
    concepts of fungal asthma (as defined above) in children, and suggest new approaches and where
    future work is needed. Although this review will focus as far as possible on children, it inevitably
    has to supplement this with adult experience and animal and cellular models where paediatric data
    are not available. Prior to writing this manuscript, a literature search was performed while using
    the search term limited to English Language papers,
    which was supplemented from the author’s personal archive of references.
  2. Definition of SAFS and Fungal Bronchitis
    2.1. SAFS in Adults
    SAFS was first defined in adults [11], and it has been suggested that it is a more severe
    phenotype than seen in unsensitized patients. For the purposes of the definition of SAFS, severe
    asthma is defined as treatment with 500 mcg Fluticasone/day or equivalent, or continuous oral
    corticosteroids, or four prednisolone bursts in the previous 12 months or six in the previous two
    years (as with so many definitions of severity, the figures are fairly arbitrary). The immunological
    J. Fungi 2019, 6, 55 3 of 17
    criteria for SAFS in adults also include a total immunoglobulin (Ig)-E < 1000, and negative IgG
    precipitins to Aspergillus fumigatus (AF) because allergic bronchopulmonary aspergillosis (ABPA) is
    a diagnostic consideration in adults, and in order to differentiate between ABPA and SAFS.
    Additionally, there needs to be evidence of sensitization (skin prick test wheal (SPT) ? 3 mm,
    specific IgE (sIgE) ? 0.4) to at least one of seven fungi, namely AF, Cladosporium herbarum, Penicillium
    chrysogenum (notatum), Candida albicans, Trichophyton mentagrophytes, Alternaria alternate, and Botrytis
    cinerea. The question as to whether sensitization is best determined by sIgE or SPTs was addressed
    in 121 patients with severe asthma (British Thoracic Society/SIGN steps 4 and 5) who underwent
    both tests to all the above fungi, except Trichophyton mentagrophytes [12]. Fungal sensitivity was very
    common, but concordance between skin prick tests and sIgE tests was poor (77% overall, but only
    14–56% for individual fungi). Hence, both of the tests need to be undertaken to rigorously diagnose
    SAFS.
    2.2. SAFS in Children
    There is no consensus definition of SAFS in children. Empirically, we define SAFS as severe,
    therapy resistant asthma [13] (STRA, with any pattern of symptoms), and we have used the same
    sensitization criteria as in adults, although in fact in a clinical setting we usually can only test for
    AF, Cladosporium and Alternaria alternate. For reasons that are unclear, ABPA is rarely, if ever, seen
    in children with asthma, despite being relatively common in children with CF [14], and so we do
    not adopt the IgE and IgG precipitin criteria of the adult definition. It is likely, but unproven, that
    there will also be discordance between sIgE and SPT results in children also [15], so both tests are
    needed.
    Table 1 contrasts the diagnosis of SAFS in adults and children.
    Table 1. Diagnostic criteria for severe asthma with fungal sensitization (SAFS) in adults and
    children.
    Fungal Sensitization
    (Positive Skin Prick Test
    and/or Specific IgE to One or
    More Fungus)
    Other Adult Criteria
    Other Paediatric
    Criteria
    Aspergillus fumigatus
    Cladosporium herbarum
    Penicillium chrysogenum
    (notatum)
    Candida albicans
    Trichophyton mentagrophytes
    Alternaria alternate
    Botrytis cinerea
    Treatment with 500 mcg Fluticasone
    Propionate/day, or Continuous oral
    corticosteroids, or 4 prednisolone bursts in
    12 months or 6 bursts in 24 months
    Severe, therapy
    resistant asthma
    (ERS/ATS Task Force
    criteria)
    IgE < 1000 IgE can be any level
    Negative IgG precipitins to Aspergillus
    fumigatus
    IgG precipitins to
    Aspergillus fumigatus
    can be positive or
    negative
    J. Fungi 2019, 6, 55 4 of 17
    2.3. Beyond SAFS: Fungal Detection in the Airway, Fungal Bronchitis and Asthma
    There is no requirement to detect fungi within the airway in order to diagnose SAFS, although
    fungal infection might be part of the syndrome. However low-grade fungal infection might drive
    asthma without inducing sensitization, for example, by the release of tissue damaging enzymes
    disrupting epithelial barrier function (below). In CF, AF bronchitis is associated with worse
    outcomes [16–18], giving biological plausibility to this mechanism in asthma. The isolation of
    fungus from airways of SAFS patients is unsurprisingly very common. AF sputum positivity by
    PCR was 70% in SAFS patients not taking anti-fungals [19], but the frequency was reduced in those
    prescribed these medications, and in a small subgroup in whom serial samples were obtained,
    itraconazole therapy resulted in sputum reverting from a positive to negative PCR. The
    sensitization to multiple molds is also common in asthma. In one study, 60% of patients were polysensitized,
    most frequently to Aspergillus fumigatus (32%) and A. Alternata (28%), Penicillium
    chrysogenum, Penicillium brevicompactum, Cladosporium cladosporioides, and Cladosporium
    sphaerospermum [20,21]
    There is also the issue of how intensively the presence of fungi should be sought. CF
    definitions are largely based on positive cultures, although whether repeated cultures or a single
    culture is needed for diagnosis is controversial. Much of the focus has been on AF, not least because
    it grows at 37 degrees (body temperature) and the spores are aerodynamically well suited to
    lodging in the lower respiratory tract, but as already stated, many other fungi may be important. In
    a study in which 69 adults underwent FOB and BAL, no fewer than 86% had fungi detectable by
    PCR on BAL, 46% of which were AF. Although a positive BAL was associated with increased BAL
    and plasma cytokines, there was no relation to asthma severity [22]. Molecular techniques may be
    even more sensitive. This study suggests that, the harder fungi are sought, the more they will be
    found. This group reported no increased asthma severity in SAFS adults; and importantly,
    potentially broadened the spectrum of fungi to which the patient may be sensitized.
    2.4. Fungal Asthma or Fungal Asthmas?
    It should be noted that the danger of umbrella definitions is that it could be taken to assume
    that all fungi have equal effects. The magnitude of the effects might be different, and will likely also
    be dependent on levels of exposure, but, more importantly, the pathophysiological pathways may
    be different. Clearly, if the approach is treatment with anti-fungals, this is irrelevant, but any
    molecular therapies may need to be fungus-specific (below).
  3. Paediatric and Adult Severe Asthma and the Atopies: Important Differences Relevant to
    Fungal Asthma
    The vast majority of children with severe asthma are markedly atopic [23], with multiple
    sensitizations to aeroallergens, such as house dust mite, grass and tree pollens, cockroach, and furry
    pets. By contrast, much severe adult asthma is neutrophilic, often in the obese and with other comorbidities,
    and with a female preponderance [24,25]. It is also increasingly being realized that
    atopy is not ‘all-or-none‘ and can be quantified [26]. Different atopies have differing significances
    [27–29]. Furthermore, complex interactions between allergens may be more important than
    individual results [30]. Sensitization to fungi is one part of the atopies; the question is, whether
    there is a discrete entity of SAFS in children, or whether fungal sensitization is one facet of asthma
    with polysensitzation to aeroallergens; to some extent, this remains unresolved. It might also be
    that the significance of fungal sensitization will be different in adults, and more likely to be a
    discrete entitity rather than mark of multiple sensitization, and this needs further exploration.
    However, the issue of anti-fungal treatment for paediatric SAFS is more one of ‘does it work?‘
    rather than ‘should it work?‘
    J. Fungi 2019, 6, 55 5 of 17
  4. Epidemiological Data: Associations between Fungi and Asthma Severity
    4.1. Cross-Sectional Studies
    Most of the big studies are in adults. The European Community Respiratory Health Survey
    [31] studied 1132 adults aged 20–44 years with current asthma. The frequency of mold sensitization
    (Alternaria alternata or Cladosporium herbarum, or both) increased significantly with increasing
    asthma severity across Europe, but there was no association between asthma severity and
    sensitization to pollens or cats. However, Dermatophagoides pteronyssinus sensitization was also
    positively associated with asthma severity. Thus, mold sensitization was highly associated with
    severe asthma in adults, but not uniquely so. In a systematic review and meta-analysis of 20 studies
    from 13 African countries [32] the mean asthma prevalence was 6%. The prevalence of fungal
    sensitization, mostly on skin prick testing, ranged from 3% to 52%, mean 28% with a pooled
    estimate of 23.3%. Aspergillus species were commonest. The prevalence of ABPA was estimated at
    1.6–21.2%. A similar study related fungal allergy to asthma severity, and there were no paediatric
    data.
    Another such study in severe asthma (GINA step 4 or 5 treatment) [33] enrolled 124 patients. A
    variety of markers were collected, including spirometry, exhaled nitric oxide, serum cytokines, and
    IgE. Fungal sensitization was assessed from IgE specific to fungal allergens (AF, Alternaria, Candida,
    Cladosporium, Penicillium, and Trichophyton species and the Schizophyllum commune). Thirty-six of
    124 patients (29%) were sensitized to at least one fungal allergen, most commonly Candida (16%),
    AF (11%), and Trichophyton (11%). Early-onset asthma (<16 years of age) was more common in
    patients with fungal sensitization (45% vs 25%; p = 0.02, see below). Interleukin-33 levels were also
    higher in patients with fungal sensitization, as discussed in more detail in the sections on
    pathophysiology. Asthma Control Test scores were worse in patients with multiple when compared
    with single fungal sensitizations and non-sensitized controls.
    4.2. SAFS and Control of Asthma
    Adult SAFS patients are more likely to have uncontrolled symptoms [34–39]. In a retrospective
    review of urban adult asthma patients, total serum IgE was highest in the 53 patients (17.3%) with
    fungal sensitization (median, 825 IU/mL vs. 42 non-atopic (n=137, 44%) vs. 203 other allergen
    sensitized (n=117, 38.1%), p < 0.001). The fungal sensitized patients were more likely to have been
    admitted to the intensive care unit (ICU) admission and been ventilated (13.2% vs. 3.7% non-atopic
    vs. 3.4% other sensitization p = 0.02; and 11.3%, 1.5%, and 0.9%, respectively, for ventilation, p <
    0.001). There are two possible interpretations of these data; firstly, polysensitized atopic asthmatics
    do worse, or that fungal sensitization is a discrete entity and an independent risk factor for bad
    outcomes.
    A study [40], which evaluated 206 adults with severe asthma (GINA step 4 or 5 treatment,
    mean age 45 ± 17 years, 99 [48%] male), of whom 78% had a positive SPT to one or more allergens.
    The most common allergen reported was house dust mites (Blomia tropicalis, Dermatophagoides
    pteronyssinus and Dermatophagoides farinii), but 11.7% were sensitized to Aspergillus species, and this
    was associated with uncontrolled asthma. In particular, Aspergillus sensitization was independently
    associated with the need for ?2 steroid bursts in the past year (odds ratio 3.05, 95% confidence
    interval 1.04–8.95). There was no association between asthma control and corticosteroid bursts with
    sensitization to any other allergen. Importantly, this study suggests that all fungi do not necessarily
    have equivalent effects.
    4.3. SAFS and Asthma Attacks: Children
    Paediatric data are much scantier, but the conclusions are very similar. A German group
    reviewed 207 children with a diagnosis of asthma of varying severity (25% had mild, 31%
    moderate, and 44% severe; 26% had a previous history of hospitalization for an asthma attack [35]).
    Alternaria was the leading mold causing sensitization, but this did not correlate with hospitalization
    J. Fungi 2019, 6, 55 6 of 17
    due to asthma attacks or other parameters of asthma severity. The prevalence of Alternaria
    sensitization increased with age and there was a significant association with the sensitization to
    other molds and aeroallergens, grass pollen, and cat epithelia. Alternaria sensitization in this study
    was thus not a risk factor for severe asthma and hospitalization. However, it should be noted that
    the risk might be a composite, both of sensitization, but also level of exposure; to take an absurd
    example, a sensitized patient who never subsequently encountered the allergen could not have an
    asthma attack triggered by that allergen.
    The Melbourne Air Pollen Children and Adolescent study [41] recruited 644 children and
    adolescents (aged 2–17 years) that were hospitalized for asthma and showed that exposure to
    Alternaria, less well known taxa, including Leptosphaeria, Coprinus, and Drechslera, and total spore
    counts were significantly associated with admissions for asthma independent of rhinovirus
    infection. Surges of spores of Alternaria, Leptosphaeria, Cladosporium, Sporormiella, Coprinus, and
    Drechslera were associated with significant effects delayed for up to three days, and Cladosporium
    sensitization was associated with significantly greater effects than the other fungi. Importantly, this
    study broadens the range of fungi that might need to be considered as part of fungal asthma,
    although the alternative explanations are that the effects were not mediated by allergic
    sensitization, or less likely, that that these spores were merely possibly markers of some
    unidentified root cause.
    4.4. SAFS and Lung Tissue Destruction
    In a cross-sectional study [42], 329 (76.3%) of adult asthmatics were sensitized to at least one
    fungus and this was related to the development of lung destruction, as assessed by postbronchodilator
    spirometry and computed tomographic (CT) scans. The sensitization to AF and/or
    Penicillium chrysogenum was associated with a lower first second forced expired volume (FEV1)
    when compared with those not sensitized, independent of atopic status, and an increased frequency
    of CT abnormalities, bronchiectasis, tree-in-bud, and collapse/consolidation. Cluster analysis
    identified three clusters: (i) hypereosinophilic hypothetically, true SAFS; (ii) high immunological
    biomarker load and high frequency of radiological abnormalities (hypothetically, fungal bronchitis
    dominant; and, (iii) low levels of fungal biomarkers (fungi not relevant). The authors concluded
    that AF sIgE was a risk factor for lung damage irrespective of ABPA.
    4.5. Fungi and Risk Assessment
    GINA and other guidelines have rightly stressed the importance of risk assessment as well as
    asthma control. There is no question that fungal sensitization is a marker of future risk of poor
    control and asthma attacks. Whether this is true for fungal bronchitis, as it is in CF, has yet to be
    explored.
  5. Clinical Features of SAFS in Children
    We have reported the largest, most detailed series of children with SAFS [43]. We studied 82
    children (median 11.7 years) with severe, therapy resistant asthma (STRA), who had undergone a
    protocolised series of investigations [44–46], including fibreoptic bronchoscopy (FOB),
    bronchoalveolar lavage (BAL), and endobronchial biopsy (EBx). Thirty eight were defined as SAFS,
    with a specific IgE or SPT to AF, Alternaria alternate or Cladosporium (in practice, we do not have
    access to testing for other fungi). We also found that children with SAFS had an earlier onset of
    symptoms (0.5 as compared with 1.5 years), a higher IgE (637 vs. 177) and were sensitized on
    testing sIgE to more non-fungal inhalant allergens, when compared with non-SAFS STRA. They
    were more likely to be prescribed maintenance oral corticosteroids (42% vs. 14%, p = 0.02).
    However, on BAL and EBx, the severity of airway inflammation and remodelling (absolute
    thickness of reticular basement membrane thickness and airway smooth muscle mass) did not
    differ between SAFS and control STRA, despite the greater use of anti-inflammatory medications.
    J. Fungi 2019, 6, 55 7 of 17
    Eight of 10 (80%) SAFS children responded to omalizumab, similar to STRA controls (11/18, 84%, p
    = NS). Mepolizumab was not licensed in children at the time of this study.
    Another paediatric study enrolled 64 children, of whom 25 (39%) had evidence of sensitization
    to at least one fungus [47]. Nineteen of 25 (76%) sensitized children had severe persistent asthma
    when compared to 13 of 39 (33%) non-sensitized (p = 0.0014). Nineteen of 32 (59%) severe persistent
    asthmatics had fungal sensitization, and these also had higher serum IgE and worse spirometry.
    Bronchial biopsy of sensitized children revealed that these children exhibited basement membrane
    thickening and eosinophil infiltration on bronchial biopsy.
    In a USA study of 126 children, Alternaria skin test reactivity was associated with severe,
    persistent asthma. Importantly, this was an independent risk factor to that of the total positive skin
    tests, suggesting there is an independent effect of this fungus unrelated to degree of atopy [48].
  6. Treatment of SAFS and Fungal Asthma
    The possible aspects of treatment are: (a) the reduction of allergic inflammation; (b) reduction
    of fungal burden; (c) reduction of tissue damage; and, (d) modulating the pro-inflammatory effects
    of tissue destruction. Most focus has been on the reduction of fungal burden, but without
    necessarily ensuring that there is a fungal infection.
    6.1. Adult Data
    Most of the data on antifungal therapy are in adults, and the results are conflicting. The FAST
    study [11] enrolled 58 adults into a double blind, randomized controlled trial of oral itraconazole or
    placebo for 32 weeks, with a follow up period of 16 weeks. The primary end point was the Asthma
    Quality of Life Questionnaire (AQLQ), with secondary endpoints being rhinitis score, total IgE and
    respiratory function. The study was positive, with improvements in AQLQ and rhinitis scores, an
    improved morning peak flow (20.8 l/min.) with itraconazole, and total IgE dropped (-510 iU
    itraconazole when compared with +30 placebo). Seven patients in the itraconazole group, and two
    placebo patients discontinued treatment. Interestingly, 60% had big improvements in QoL with
    itraconazole. The benefits of itraconazole declined rapidly in the washout period. By contrast,
    EVITA3 was a randomized, double blind, placebo controlled trial of Voriconazole in SAFS [49]. Of
    note, Voriconazole does not increase steroid bioavailability, unlike itraconazole [50,51]. The study
    duration was three months with a nine-month follow period. Fifty-six adults with SAFS were
    recruited. The inclusion criteria were at least two severe asthma attacks (defined as the prescription
    of oral corticosteroids) in the previous year, and a positive specific IgE or skin prick test to AF. The
    voriconazole levels were measured to optimize therapy. The primary endpoints were quality of life
    and asthma attacks. The study was negative. Neither trial mandated a positive airway fungal
    culture. In another report, 41 patients were studied retrospectively [52]. In those who received
    treatment (n = 32), this was with any of terbinafine, fluconazole, itraconazole, voriconazole, or
    posaconazole combined with standard treatment, by comparison with nine patients who had
    standard asthma therapy only. Those that were treated with anti-fungals showed improvement in
    Asthma Control Test, peak flow rate, and IgE. The response was better with longer treatment
    periods, and it was well tolerated, but relapse was common after the discontinuation of treatment.
    It should be noted that all of these data largely predate the widespread introduction of biological
    and, therefore, should be interpreted with caution in light of new therapies [53].
    In another study [54], 110 STRA GINA stage 4 adult asthmatics were randomly assigned to 200
    mg itraconazole twice a day or 10 mg prednisolone once daily for four months. There was no
    requirement for the demonstration of fungal sensitization or any other manifestation of fungal
    asthma. The study was not blinded. 71% of the itraconazole group improved and there were very
    few side-effects, whereas there was minimal change with prednisolone.
    In terms of acute asthma, there is a single case report of an 83 years old woman [55], with a 33-
    year history of asthma prescribed inhaled and oral corticosteroids. She presented with an acute
    attack of wheeze that did not respond to oral corticosteroids and antibiotics. She was found to
    culture AF in her sputum, a positive AF sIgE and IgG precipitins, and a positive galactomannan.
    J. Fungi 2019, 6, 55 8 of 17
    Voriconazole was added with a good response. Perhaps the most likely explanation is that this was
    treating acute AF bronchitis in an immunosuppressed adult. There is no general role for antifungals
    in acute asthma.
    6.2. Paediatric Data
    There are no randomized controlled trials of treatment in children. On general principles, we
    try to minimize fungal exposure, especially advocating for rehousing if there is visible mold in the
    house; we would check any nebulizers which might be being used for fungal contamination; and
    we would advise against children going into stables and barns [56], where mold abounds.
    However, although the reducing the burden of fungal allergen exposure seems sensible, the
    relationship between mold exposure, mold sensitization, and asthma severity is complex.
    Approximately 90% of homes in one case control study were contaminated with mold [20]. The
    sensitization to AF, but not to other molds, was associated with asthma severity. Whether or not the
    child was sensitized, AF and Penicillium spp in dust was associated with severe asthma; the latter
    was associated with worse lung function. The lessons of this study are that environmental AF
    exposure should be minimized, and that not all molds have the same effects. However, although
    exposure to mold may limit airway infection, it should be borne in mind that allergen reduction
    strategies have sometimes had unexpected effects. In some cases, high level exposure might induce
    tolerance, and reduction in levels lead to increased sensitivity; and there is marked variation
    between allergens in the relationship between environmental concentrations and likelihood of
    sensitization or tolerance [57].
    Additionally, we would also optimize standard asthma management and treatment [6–8],
    including treatment with omalizumab and mepolizumab if indicated, before going on to ‘beyond
    guidelines’ therapy with antifungals. Anecdotally, a child with refractory asthma, persistently
    abnormal spirometry, total E >20,000 IU/mL, and severe airway eosinophilia was sensitized to
    multiple fungi and responded dramatically to itraconazole [58]. Additionally, anecdotally,
    omalizumab might effectively treat the occasional case of SAFS [59], alone or combined with
    itraconazole which may be used to reduce IgE levels into the omalizumab range [60]. Also
    anecdotally, we have seen the occasional SAFS child who appeared to improve with antifungals.
    6.3. Conclusions: What is the Role of Antifungals in SAFS?
    It is suggested that the individual facets, or treatable traits of fungal asthma, are determined on
    an individual basis and a bespoke treatment plan developed. Clearly, the evidence for the use of
    antifungals is conflicting and of low quality. Part of the reason might be that SAFS as
    conventionally declined does not require the presence of fungal bronchitis. It is difficult to see how
    anti-fungal therapy would benefit SAFS if there were no fungal infection, and symptoms were
    solely due to sensitization to fungal spores. Logically, future trials of anti-fungal therapy in
    SAFS/fungal asthma should mandate the presence of fungal bronchitis.
    Our current approach is to address environmental exposures and optimize standard therapy in
    children with SAFS. If asthma control is optimal and there are no other markers of ongoing risk,
    such as a persistently raised exhaled nitric oxide or a past history of really severe attacks, with no
    present side-effects, then we would not use antifungals. However, if asthma control remains
    suboptimal, or significant risks persist, then we would consider adding an antifungal, such as
    itraconazole. It is important to note that there is a potential interaction between corticosteroids and
    azoles at the cytochrome p450 level [61], such that the combination of itraconazole and inhaled
    budesonide has led to iatrogenic Cushing Syndrome [50,51].
  7. Risk Factors for SAFS: Genetic Studies
    Although there is expanding literature on the genetic associations of ABPA, SAFS has been
    little investigated. There might indeed be genetic factors that are associated with SAFS, but, to my
    knowledge, there has been no large scale Genome Wide Association Study (GWAS) to confirm or
    J. Fungi 2019, 6, 55 9 of 17
    otherwise this suggestion. In a small, preliminary study [62], 325 haplotype-tagging single
    nucleotide polymorphisms (SNPs) in 22 previously suggested candidate genes were studied in
    SAFS (n = 47), atopic asthmatics (n = 152), and healthy control patients (n = 279). There were
    significant associations of Toll-like receptors (TLR) 3 and 9 (TLR3), C-type lectin domain family
    seven member A (dectin-1), IL-10, mannose-binding lectin (MBL2), CC-chemokine ligand 2 (CCL2)
    and CCL17, plasminogen, and the adenosine A2a receptor, different from those reported in asthma
    complicated by ABPA. Some of these hits are supported by cell and animal data (below). The main
    weakness of this study was the absence of a second validation cohort, without which the findings
    are, at best, preliminary. In an initial small study comprising 76 adults with chronic cavitatory
    pulmonary aspergillosis (n = 40), ABPA (n = 22), and SAFS (n = 14), no genetic associations of SAFS
    could be determined, unsurprisingly with such a small number of patients [63]. However, in one
    intriguing study, six SAFS children were heterozygous for a 24-base pair duplication in the CHIT1
    gene [64]. This duplication associates with an increased susceptibility to fungal infection and
    decreased circulating chitotriosidase levels [65]. Clearly there is a need for more work in this area.
  8. Pathophysiology of SAFS and Fungal Asthma
    8.1. Introduction
    As discussed, there are two pathological mechanisms, whereby fungi, especially AF, can cause
    disease in children with asthma [8]. These are as a source of allergen(s) to which the child is
    sensitized, leading to wheeze on exposure, and driving a Type 2 inflammatory response; and, the
    release of tissue damaging enzymes by fungi that have infected the airway (not dissimilar to, for
    example, house dust mite, which is allergenic and tissue damaging), and that might also generate
    an allergic response. It should be noted that other proteins could generate an allergic response
    without requiring airway infection, for example, in sensitization to furry pets.
    Any account of the potential role of exogenous infection of any cause must consider the
    possibility that this is iatrogenic, secondary to the use of corticosteroids. It is known that systemic
    corticosteroids are immunosuppressive, and also that mucosal immunity is essential for normal
    host defence [65]. It is biologically plausible that topical steroids would be immunosuppressive, and
    indeed their use is associated with increased prevalence of tuberculosis, [66] atypical Mycobacterial
    infection [67], and, in patients with COPD, pneumonia [68]. It is virtually impossible to dissect out
    the contribution of inhaled corticosteroids (ICS) to SAFS, because, by definition, all SAFS patients
    will be prescribed ICS. In one study [69], the fungal microbiome (mycobiome) was determined on
    bronchoscopic samples. The investigators reported that the mycobiome was highly varied with the
    biggest load in severe asthmatics. Healthy controls had low fungal loads; the most common fungus
    detected was the poorly characterized Malasezziales. AF was most the common in fungus in
    asthmatics and accounted for the increased fungal burden. Corticosteroid treatment was
    significantly associated with an increased fungal load. These interesting data cannot unravel
    whether inhaled corticosteroids caused SAFS, or SAFS led to the prescription of more inhaled
    corticosteroids.
    8.2. Cell and Animal Studies
    A number of different pathways have been implicated in SAFS, including the pattern
    recognition receptors (PRRs) TLR3, TLR9, and Dectin-1 and IL-7, Il-10, IL-22, CCL2, and CCL17
    [70,71]. IL-33 has been implicated in both adult [36] and paediatric SAFS [5]. IL-33 is an epithelial
    alarmin, together with IL-25 and TSLP. It is a member of the eleven member IL-1 family of
    cytokines. Of these, seven are proinflammatory (IL-1?, IL-1?, IL-18, IL-33, IL-36?, IL-36?, and IL-
    36?) and four probably immunomodulatory (IL-1 receptor antagonist [IL-1RA], IL-36Ra, IL-37, and
    IL-38). A recent manuscript [72] demonstrated that IL-1? and IL-1? are elevated in the BAL and
    sputum from adult SAFS patients. The same group used a murine model utilizing the AF challenge
    to show that IL-1R1 signaling promotes increased airway hyper-responsiveness and neutrophilic
    inflammation associated with type 1 (IFN-?, CXCL9, CXCL10) and type 17 (IL-17A, IL-22)
    J. Fungi 2019, 6, 55 10 of 17
    responses, each exacerbated in IL-1RA?/? mice. The administration of human recombinant IL-1RA
    (Kineret/anakinra) abrogated these responses, all suggesting that IL-1R1 signaling via type 1 and
    type 17 responses is an important and potentially treatable pathway of SAFS.
    A murine model further explored the links between Alternaria and asthma [73]. Wild-type and
    mice lacking the IL-33 receptor (ST2?/?) underwent inhalational challenge with inhaled house dust
    mite, cat dander, or Alternaria. Mice that were sensitized with house dust mite were subsequently
    challenged with Alternaria (with or without serine protease activity having been knocked down),
    and inflammation, remodeling, and lung function assessed 24 h after the challenge. Only Alternaria
    possessed intrinsic serine protease activity that led to the release of IL-33 into the airways via a
    mechanism that is dependent on the activation of protease activated receptor-2 and adenosine
    triphosphate signaling. This led to more pulmonary inflammation relative to that produced by the
    house dust mite challenge. IL-1? and matrix metalloproteinase (MMP) 9 release were also features
    of Alternaria challenge. Furthermore, Alternaria triggered a rapid, augmented inflammatory
    response, mucus hypersecretion, and airway obstruction. The effects of Alternaria were critically
    dependent on ST2 signaling. Hence, Alternaria-specific serine protease activity resulted in rapid IL-
    33 release, leading to TH2 inflammation and exacerbation of allergic airway disease.
    Alternaria proteases may have an important role. One study [74] used cells from normals or
    patients with severe asthma. They used both 16HBE cells and fresh bronchial epithelial cells
    cultured to air-liquid interface (ALI), and challenged them apically with extracts of Alternaria in
    order to further explore the role of Alternaria proteases. Alternaria extract protease activity was

Keywords: atopy; aspergillus bronchitis; fungal sensitization; itraconazole; severe asthma;
voriconazole

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Defeating Asthma Series Announced for World Asthma Day, May 5, 2020

 

World Asthma Foundation is supporting care of Asthma and asthmatics around the world through a new series focused on Defeating Asthma with the aim of shining a spotlight on getting to a cure

The World Asthma Foundation (WAF) exists for education and advocacy for people with asthma who suffer medically with health issues that make them highly vulnerable to the COVID-19 virus and other diseases.

We’ve hunkered down close to home here at the WAF. While doing so, we’re poring over volumes of available Asthma research data to share our understanding of the root causes of Asthma with emphasis on Severe Asthma.

Our ultimate goal is to understand the root cause of Severe Asthma (already considered a pandemic by many) while we aim for a cure. By banding together with other Asthmatics, including those that care about Asthmatics and clinicians that treat, we can defeat Asthma and we can do so now.

Why this Matters:

  • Asthma is not one disease but many and the causes underlying its development and manifestations are many including environmental issues
  • Asthma has reached pandemic levels around the globe
    Asthma is a chronic lung disease that affects over 300 million worldwide
  • The projected rate will reach 400 million by 2025
  • Environmental exposures have been proven to play a significant role in the development of asthma and as triggers
  • Asthma is believed to be determined by a complicated set of one’s own genetics and environmental exposures including a multitude of toxic chemicals and the overuse of antibiotics
  • In the U.S., African Americans are almost three times more likely to die from asthma-related causes than the white population
  • Australia reported the highest rate of doctor diagnosed, clinical/treated asthma, and wheezing
  • Defining asthma remains an ongoing challenge and innovative methods are needed to identify, diagnose, and accurately classify asthma at an early stage to most effectively implement optimal management and reduce the health burden attributable to asthma
  • According to the U.S. Centers for Disease Control, The total annual cost of asthma in the United States, including medical care, absenteeism and mortality, was $81.9 Billion a year.

“We can move the needle by taking action now to make the difference for those that suffer from Asthma.” – Alan Gray, Director WAF Australia

What you can expect from the WAF Severe Asthma Series

Follow along with the series (click here) as we cover a variety of topics of interest to Asthmatics. 

  • What are the various types of Severe Asthma
  • What drives Severe Asthma
  • Impact of the environment on Severe Asthma
  • For additional on Asthma and the Microbiome click here 
  • What are the treatment options for Severe Asthma
  • Real world case studies with in-depth analysis
  • University research
  • Live expert podcast and interviews
  • Healthy lifestyle resources
  • Asthma advocacy guide and communication strategies for talking with your medical team

WAF will bring fresh perspectives from experts in the field that affects Asthmatics.

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Managing Asthma during COVID-19: An Example for Other Chronic Conditions in Children and Adolescents

 

The novel coronavirus COVID-19, caused by the pathogen SARS-CoV-2, has now spread around the globe with over 1.8 million individuals affected and over 110,000 deaths internationally.(1, 2, 3, 4) As of April 12, 2020 there are 530,830 cases in the U.S. with over 20,000 deaths(2,3) The Institute for Health Metrics and Evaluation (IHME) has predicted that this pandemic could exceed current healthcare capacity in the United States (US) with a total of 81,114 deaths (95%UI 38,242 to 162,106) through August 2020.(5)

Asthma is one of the most common chronic diseases of childhood in the United States. Data from the U.S. Department of Health and Human Services notes that asthma prevalence increased between 2001 and 2010 and is now at its highest prevalence ever (overall 8.4% in 2010).(6) In the US, approximately 7 million children have asthma.(6) The morbidity of asthma in the US is high, and is higher in children than adults. Children missed 10.5 million school days due to asthma in 2008; there were 6.7 million primary care visits related to asthma and 600,000 asthma-related ED visits for children in 2007.(7)

Multiple guidelines have emerged from international societies on the management of medical care during COVID-19 which include a section on pediatric asthma, including a North American guideline on contingency planning for allergy and immunology clinics during a pandemic and a Canadian Pediatric Society statement on asthma management during COVID-19.(8,9) Due to the high prevalence of asthma in the United States, which is at the current epicenter of a global pandemic, the goal of this commentary is to provide an overview of what is known, and what is yet to be learned, about COVID-19 and pediatric asthma.
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Differentiating Asthma from COVID-19

Symptoms of COVID-19 can be similar to those of worsening asthma, or an asthma exacerbation. Dry cough and shortness of breath, commonly seen in asthma, are among the most common presenting symptoms of COVID-19 in case series of children admitted to the hospital in China, as well as in available CDC data in the U.S.(10, 11, 12)

Fever, a common presenting symptom of COVID-19, may help differentiate COVID-19 from an asthma exacerbation, although fever can be present in other virus-triggered asthma exacerbations as well.(3,10, 11, 12) Other less common symptoms of COVID-19, better described in the adult population, may help differentiate COVID-19 from asthma and include myalgia, confusion headache, pharyngitis, rhinorrhea, loss of sense of smell and taste, diarrhea, nausea and vomiting.(12) A travel history, close contact with someone infected with COVID-19, and absence of a prior atopic history in a child also help to differentiate the two.

Since there is substantial overlap between the clinical presentation of worsening asthma and COVID-19 and increasing community spread lessens likelihood of known contact with a case, screening for COVID-19 is required if available in any asthmatic child who comes to medical attention with worsening cough or shortness of breath.(8,13)

The Role of Asthma in COVID-19 Morbidity and Mortality

There is a theoretical risk that infection with COVID-19 in an asthmatic child may increase the risk of pneumonia or acute respiratory disease. (14) As a result, the CDC lists moderate to severe asthma as a risk factor for COVID-19 morbidity and mortality.(14) However, to date the literature is ambiguous on whether pre-existing asthma increases the risk of either COVID-19 infection, or morbidity/mortality due to COVID-19, in children.

The evidence on COVID-19 risk factors derives largely from the adult population. Four case series, all from Wuhan, China, of adults admitted to hospital with COVID-19 did not list asthma as an underlying pre-existing condition in any of those patients.(12,15, 16, 17) In a large case series of 1099 adult patients from 552 hospitals in 30 provinces in China, asthma was not listed as a pre-existing condition in any of the patients described.(18) In contrast, recent data released from the CDC of U.S. hospitalizations in March,2020 notes that 27.3% of adults 18-49 years of age who were hospitalized with COVID-19 had a history of asthma.(3) In adults aged 50-64 years of age hospitalized for COVID-19 asthma was present in 13.2% and in those 65 years or older asthma was present in 12.9%.(3,19) As a result, the American Academy of Allergy, Asthma & Immunology (AAAAI) notes that ‘those with asthma in the 18-49 year old age range may be at increased risk of hospitalization due to COVID-19.’(19)

Although there is a paucity of literature on pediatric risk factors, the case series to date from Wuhan on hospitalized pediatric cases don’t list asthma as a pre-existing risk factor for morbidity or mortality.(10,11) It is further reassuring that children appear to be at lower risk of COVID-19 morbidity and mortality than the adult population in general, although severe infection still can occur.(13,20) The CDC morbidity and mortality report notes that among the 149,082 reported U.S. cases of COVID-19 for which age is known, only 2572 (1.7%) occurred in children 18 years and younger.(3) Although among the patients with information on underlying conditions, 23% had at least one underlying condition such as asthma, only 5.7% of children infected with COVID-19 required hospitalization (compared with 10% of adults aged 18-64 years) and only 3 deaths were reported in children (<1% of pediatric cases). In a case series from China of 72,000 cases, approximately 1% were children aged 0 to 18 years of age with only 1 death reported in the adolescent population (and none in children under the age of 10 years).(13,21)

Another risk in children with asthma is that infection with COVID-19 could trigger a viral-induced asthma exacerbation. There is minimal literature on this risk from COVID-19, but there are data on the risk of asthma exacerbations triggered from other coronavirus infections, with mixed findings. Severe acute respiratory syndrome (SARS), due to human coronaviruses HCoV-229E and HCoV-OC43, did not cause an increase in asthma exacerbations in children during the 2002 epidemic, nor induce bronchial hyperreactivity or eosinophilic inflammation.(22) In fact, paradoxically, asthma exacerbations actually decreased during that time, which was attributed to improvements in hygiene measures related to the epidemic.(22) However, in contrast, non-epidemic coronaviruses are found commonly in the respiratory tracts of children with an asthma exacerbation and have contributed to bronchial hyper-reactivity and eosinophilic inflammation.(23, 24, 25, 26)

In summary, based on available information to date, it is unclear whether there is a significantly increased risk of COVID-19 morbidity among asthmatic children.(8,9) It is also unknown whether asthma medications such as high-dose inhaled corticosteroids or asthma biological therapies pose a risk in managing COVID-19 infections. Before any definitive conclusions can be drawn, larger scale data are required from pediatric populations, and from heterogeneous locations that have been impacted by COVID-19. It also remains unclear if COVID-19 increases the risk of asthma exacerbations. As a result, good asthma control is essential as a precautionary measure during this time.(8,9,13,20)
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Treatment of Asthma During COVID-19

In addition to the current burden of COVID-19, the spring season is often a time for asthma exacerbations due to emergence of seasonal aeroallergens, and other respiratory viruses.(27) The best way to prevent an exacerbation is consistent proper use of medicines to control asthma, such as inhaled corticosteroids and/or montelukast. As a result, children should remain on their current asthma medications during COVID-19.(8,9) This recommendation is supported by multiple international organizations, including the Centers for Disease Control, the Global Initiative for Asthma, and the North American consensus guideline on allergy care during COVID.(8,9,28,29) It is recommended that children not ‘step down’ any controller medication during this time unless ‘this is clearly favorable from an individual standpoint, with careful consideration of the balance between benefit and harm/burden.’(8) Other recommendations to maintain asthma control include avoiding known asthma triggers such as aeroallergens, frequent handwashing, physical distancing, and regular review of inhaler technique.(9,29) An exacerbation, if it occurred, ‘could require [children] to enter the healthcare system, which would put them at increased risk of being exposed to SARS-CoV-2 during the current pandemic.’(8)

Some biologic agents, such as omalizumab (anti-IgE) and mepolizumab (anti-IL5), are approved for use in moderate to severe asthma in adolescents(30) The current recommendation for adolescents who are using these medications is to continue their use.(8) There is no current evidence that use of these medications increases the risk of COVID-19 infection or morbidity.

If a child is using a nebulized asthma relief medication, this should be switched to a metered-dose inhaler (MDI) or dry powder inhaler (turbuhaler or diskus) under most circumstances.(8,9) Nebulization increases the risk of viral lower lung deposition.(8,9,31) It also increases the risk of infection transmission due to both stimulating a cough reflex, as well as generating ‘a high volume of respiratory aerosols that may be propelled over a longer distance than is involved in a natural dispersion pattern.’(31) It was poignantly noted in a recent editorial that ‘there is a possibility that nebulizer therapy in patients with COVID-19 infection can transmit potentially viable coronavirus to susceptible bystander hosts.’(31) The only possible reasons for a child to use a nebulizer at home during the COVID-19 pandemic are a poor response to a MDI/spacer, a child who is either uncooperative or unable to follow the directions required for MDI use, or medication shortages (which are discussed in more detail below).(8,9,31)
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Treatment of Asthma Exacerbations during COVID-19

The CDC and World Health Organization (WHO) have recommended against oral corticosteroid (OCS) use as a treatment for COVID-19.(32,33) This recommendation is based on experience with influenza, SARS-CoV, and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), where OCS use prolonged viral replication and was associated with prolonged viral clearance, increased complication rates, increased risk of mechanical ventilation and higher mortality rates.(34, 35, 36, 37) It has been noted that OCS therapy increases the risk of nosocomial infection and secondary infection.(38) However, there is a distinction between OCS use as a therapy for COVID-19, and OCS use as a treatment of asthma exacerbations.(8) There is broad consensus that asthma exacerbations should be treated aggressively and in keeping with current guideline recommendations.(9) Multiple national and international organizations such as the Global Initiative for Asthma recommend OCS use as required, and in keeping with the child’s asthma action plan, during COVID-19.(8,9,28)

The use of nebulized medications are especially discouraged in a healthcare setting, where infection transmission to other vulnerable patients is a risk.(9,31) If used, proper personal protective equipment (PPE) is required. It must also be considered that nebulized viral droplets can persist in the air for hours.(39)

For any child with asthma who is having progressive or worsening symptoms, COVID-19 screening protocols must be used to help determine their level of risk as well as the need for COVID-19 testing at an appropriate facility.(8)

For children hospitalized with an asthma exacerbation either documented or suspected to be associated with COVID-19 that is progressing, it might be decided to use one of the agents currently being considered in adults, for example, hydroxychloroquine.(40,41) or to seek compassionate release of remdesivir. There is no current data on the safety and efficacy of these agents in children and thus should be discussed in the setting of the hospital policy.(42,43) Although dosage of these medications in adolescents may be similar to adults, the appropriate adjustment for children under 12 years remains to be defined.
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Ongoing Challenges during COVID-19

Medication shortages. There is a growing medication shortage across North America, including asthma medications such as albuterol.(39) In many cases, such as with albuterol, these medications increasingly are being used in confirmed or suspected COVID-19 patients to help with respiratory issues. To help combat the shortage of albuterol specifically, the US Food and Drug Administration (FDA) approved the first generic albuterol inhaler on April 8,2020.(44) If faced with albuterol shortage, other available options include substituting other short acting beta-agonists, using an expired albuterol inhaler, and ensuring good asthma control which reduces the need for reliever medications in general.(9,39) Many of the substitute short acting beta-agonists are dry powder inhalers (diskus or turbuhaler) and as such children often need to be at least 6 years of age to produce enough inspiratory force to use these devices properly.(9,45) For adolescents 12 years and older, another option is ICS-formoterol for both maintenance and relief therapy as supported by the Global Initiative for Asthma 2019 update.(46,47) Nebulized albuterol should only be considered as a last resort, and proper infection prevention protocols need to be followed.(8,9,31) If no other medications are available, epinephrine inhalers might be considered as well, if used prudently.

Virtual visits. With the need for significant healthcare resource reallocation, as well as shortages of PPE, much of the allergy/immunology specialty has converted to largely virtual visits, or visit deferral, during COVID-19.(8) Due to the need for almost exclusively virtual visits at this time, having a peak flow meter in homes may be helpful to diagnose an acute exacerbation at home, by comparing baseline measurements with those during highly symptomatic times. There are several advantages to virtual visits, including access to specialists, removing the transportation barrier required for an in-person visit, allowing those too sick to travel to connect with a healthcare provider, and most importantly in the current context, prevention of infection transmission with in-person visits.(48)

Virtual visits should be prioritized for children who have poorly controlled asthma, have worsening asthma symptoms, or who have required dose escalations of their asthma medications in the past several months’ time.(8) It is recommended that follow-up visits for children with mild-to-moderate or well-controlled asthma be postponed during COVID-19, or converted to virtual visits if time permits.(8) It also is recommended that children of any asthma severity who have been well controlled for the past 6-12 months (no ER visits, <1 OCS dose, <2 exacerbations in the past 6-12 months) have visits deferred or converted to virtual visits (time permitting).(8) For children with moderate to severe asthma exacerbations, an in-person visit likely is necessary but as noted in the joint North American guideline on COVID-19 and allergy contingency planning, ‘If the allergy/ immunology office does not have PPE available, it would be recommended that no patients with a co-potential for an asthma exacerbation and COVID-19 be seen at that office; the patient should instead be seen at another facility capable of COVID-19 isolation which is staffed and equipped to assess and manage asthma.’(8) Recommendations may be adjusted over time, based on the duration of COVID-19 and the time required for physical distancing.

Asthma Clinical Trials. It is currently recommended that entry into any asthma clinical trial be suspended during COVID-19.(8) For asthmatic children already participating in clinical trials, consideration could be given to virtual visits if possible.(8) Procedures that require forced expiratory maneuvers such as spirometry, methacholine challenge or induced sputum samples should be postponed in order to minimize staff risk and potential room contamination. Medication withdrawal as part of research protocols also should be deferred to a later time. Consideration should be given to telephone or telemedicine visits in order to limit exposure to a medical setting.

Impact of Social Determinants of Health on Asthma and COVID-19. There are many social determinants of health that have an impact on pediatric asthma morbidity including caregiver income, physical environment including exposure to second-hand smoke, access to health services, and race/ethnicity.(49, 50, 51) There is likely an interplay between some of these social determinants of health and the impact of COVID-19 on children with asthma. It has been suggested that exposure to second-hand smoke increases COVID-19 morbidity.(52,53) Of those hospitalized in the US for COVID-19, data from the CDC indicates that 33.1% were non-Hispanic black, while they only make up 18% of the catchment area population.(3) A recent editorial notes that low-income families are at higher risk of COVID-19 as low income jobs mostly can’t be performed remotely, often don’t pay sick days, are often not associated with insurance benefits and as a result it may not be possible for these families to afford the steps necessary for physical distancing.(54)

Although the relationships between these variables needs to be further elucidated, it is possible that measures that impact social determinants of health, such as reducing exposure to second-hand smoke or improving healthcare access in low income neighborhoods, may improve prognosis in children with asthma who contract COVID-19. In addition, these families could benefit from counseling on having the appropriate amount of medications available for home during this period of restricted travel. In addition, they should check medications to be sure that none is expired.

Impact of COVID Restrictions. It is possible that children may not be severely affected by SARS-CoV-2 for some undefined reason to date, but they can still be carriers and could transmit virus to vulnerable people, including elderly relatives. Therefore, social distancing has included children, which has necessitated discontinuing school. It remains to be determined what impact this step has on children including those children with asthma. Often parents will discontinue medications in children during the summer months because they are doing well and they are out of school.(55) However, this year is different, because school was discontinued during the spring season, a time of seasonal allergen exacerbation and viral infection. School adds a certain structure to the day and there is some level of administration of asthma medication administration around the school day. Clinicians and parents should observe for potential breakdowns in adherence to controlling medications, especially in families in chaotic circumstances. The impact on education of home schooling, especially in families that lack an organizational structure remains to be seen. Finally, it has been suggested that school closure will increase the risk of childhood obesity, a known risk factor for worsening asthma.(56) Whether this occurs, and how this influences asthma control, also is yet unknown.

Conclusion

In the face of unchartered territory and unprecedented times, there remains much to be learned about the impact of pediatric asthma on the course of SARS-CoV-2 virus infection. Although adult data suggest that asthma is a risk factor for COVID-19 morbidity and mortality such a risk in children is unclear. Differentiating COVID-19 from worsening asthma, or an asthma exacerbation, is challenging. As a result, pediatricians and families have an essential role in ensuring that children with asthma maintain good asthma control during this time. Children and adolescents with asthma should remain on their current asthma medications and practice physical distancing, regular handwashing, and aeroallergen avoidance. Treatment of asthma exacerbations should include oral corticosteroids if required. Nebulized medications are not recommended at this time due to increased risk of viral transmission. Healthcare providers should remain alert for changing policies and recommendations knowledge advances.

WAF would like to thank the following for granting permission

Elsevier

Elissa M. Abrams, MD, MPH?
Department of Pediatrics, Section of Allergy and Clinical Immunology, University of Manitoba
Department of Pediatrics, Division of Allergy and Immunology, University of British Columbia
Stanley J. Szefler, MD
The Breathing Institute, Children’s Hospital Colorado and Section of Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO

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Toxicants and Asthma – Recognizing Health Advocates and Champions for Asthmatics Everywhere

Toxicants and Asthma – Recognizing Health Advocates and Champions for Asthmatics Everywhere

“Polycyclic aromatic hydrocarbons, or PAHs — Exposure can come from breathing car exhaust, fossil fuel combustion, cigarette smoke, and wood smoke, among other routes. The toxicants were linked to problems such as reduced birth weight, asthma, and lower IQ.” – Frederica Perera, Ph.D., Renowned environmental health scientist.

On behalf of the Asthma community around the globe, the World Asthma Foundation (WAF) salutes Frederica Perera as she is being honored for pioneering research, community engagement.

The NIEHS Spirit Lecture Awardee collaborates with disadvantaged groups to study how chemicals affect children and other vulnerable people.

Renowned environmental health scientist Frederica Perera, Ph.D., delivered the 2020 NIEHS Spirit Lecture on Mar. 5. Her talk was titled “Translational Research to Prevent Environmental Threats to Children: From Chemicals to Climate Change.”

Frederica Perera, Ph.D. stands at podium “NIEHS has been the main, visionary funder of our work on children’s environmental health. It’s so important to our field to have this enlightened support,” said Perera. (Photo courtesy of Steve McCaw)

Perera is a Columbia University professor and the founding director of the school’s Center for Children’s Environmental Health, which is co-funded by NIEHS. Her work focuses on pregnant women, children, and minority groups, who can be especially vulnerable to pollution.

“She is internationally recognized as a pioneer in the field of molecular epidemiology as it relates to better understanding how problems in the environment can lead to adverse health effects and disease,” said NIEHS Acting Director Rick Woychik, Ph.D.
Early-life vulnerability

In the late 1970s, after learning about an environmental disaster in Minamata Bay, Japan, Perera became inspired to pursue a scientific career in environmental health.
Rick Woychik, Ph.D. smiles at the audience from the podium “Dr. Perera has been a prolific author, with over 330 publications,” noted Woychik. (Photo courtesy of Steve McCaw)

“Women there had been eating fish that were very polluted by mercury from industrial sources,” she told the audience. “The women were fine, but their children had serious cerebral palsy-like symptoms and intellectual disorders.”

“There are 82 billion neurons in the average brain, but almost all were formed before we were born,” she said. “You can imagine how highly choreographed and complex this development is over a short time window, and how readily any external exposure — whether a physical toxicant or psychosocial stressor — could disrupt these processes.”
Frederica Perera, Ph.D. speaks to a large audience A packed audience listened closely to Perera’s lecture. (Photo courtesy of Steve McCaw)
Health effects over time

At Columbia, Perera and her colleagues seek to understand how early-life chemical exposures affect children’s health and brain development, and they look for potential long-term problems. The scientists follow cohorts of mother-child pairs in New York City (NYC), Poland, and China, tracking health effects of various substances over time.

In NYC, participants come from low-income African-American and Dominican households. Some findings from that cohort include the following.

Chlorpyrifos — Prenatal exposure to this insecticide was associated with lower birth weight, memory problems, and Parkinson’s Disease-like changes.
Phthalates — Found in cosmetics and plastic packaging, these chemicals were linked to reduced IQ in children who had been exposed to high concentrations prenatally.
Polybrominated diphenyl ethers, or PBDEs — These flame retardants were linked to reduced IQ in children who had high concentrations at birth.
Polycyclic aromatic hydrocarbons, or PAHs — Exposure can come from breathing car exhaust, fossil fuel combustion, cigarette smoke, and wood smoke, among other routes. The toxicants were linked to problems such as reduced birth weight, asthma, and lower IQ.

Many factors at play

According to Perera, understanding the effects of such exposures often is complicated by other factors, including genetics, nutrition, socioeconomic status, and climate change. She said that despite that complexity, studying individual chemicals still is beneficial.

“Most diseases require a set of sufficient causes,” Perera explained. “If we can take one of those causes out, it would be possible to prevent a child from developing a disease. Environmental exposures, by their very nature, are preventable once we identify them as harmful.”

Perera said that lowering the risks of environmental exposures will require a mix of regulatory policies, market reforms, and better data on the health and economic benefits of pollution mitigation.
Special award

“It’s a real honor for me to have the privilege to introduce Dr. Perera as this year’s recipient of the NIEHS Spirit Lecture Award,” said Woychik.

Angela King-Herbert, D.V.M. stands by Frederica Perera, Ph.D. holding an award Angela King-Herbert, D.V.M., Spirit Lecture Committee member and head of the National Toxicology Program Laboratory Animal Medicine Group, presented the award to Perera. (Photo courtesy of Steve McCaw)

The award recognizes outstanding women who balance their careers with public engagement, volunteering, and mentorship.

“She works with many different community groups to address the safety and health of children,” he said. “Dr. Perera is a fabulous communicator and is doing cutting-edge, exciting research.”

(Payel Sil, Ph.D., is an Intramural Research Training Award fellow in the NIEHS Inflammation and Autoimmunity Group.)

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Study assesses asthma treatment options in African American children and adults

Use of long-acting bronchodilators had no impact for some African American children.

A new study of African Americans with poorly controlled asthma, found differences in patients’ responses to commonly used treatments. Contrary to what researchers had expected, almost half of young children in the study responded differently than older children and adults, and than white children in prior studies.

“We shouldn’t assume that current treatment strategies for asthma are ideal for all African Americans since for many years that population was not adequately represented in research,” said Elliot Israel, M.D., senior study author and director of clinical research in the Pulmonary and Critical Care Medicine Division at Brigham and Women’s Hospital. “We found that almost half of the African American children studied responded better to increasing the dose of inhaled corticosteroids than adding a long-acting bronchodilator. Thus, adding a long-acting bronchodilator may not be the right answer for nearly half of African American children.”

The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, funded this research to assess the best approach to asthma management in African Americans, who suffer much higher rates of serious asthma attacks, hospitalizations, and asthma-related deaths than whites. The findings appear today in the New England Journal of Medicine.

The researchers examined how to escalate or “step-up” asthma treatments for African Americans whose asthma had not been treated adequately with low doses of inhaled corticosteroids, the standard starting treatment. The treatment choices in the trial included increasing the dose of inhaled steroid, adding a long-lasting bronchodilator (used to help open airways), or both.

Based on prior studies, investigators expected that increasing the inhaled corticosteroid dose would lead to improvement in most African American children needing treatment for asthma.

The researchers found that in children under 12 years of age, either approach was effective: nearly half (46%) responded better to increasing the inhaled corticosteroid dose alone and just as many (46%) responded better to increasing the inhaled corticosteroid dose and adding a long-lasting bronchodilator.

“This study suggests that we cannot look at results from one population and extrapolate the findings to African Americans or any other group,” said Michael Wechsler, M.D., principal investigator for the NHLBI-funded Best African American Response to Asthma Drugs (BARD) study and professor of medicine at National Jewish Health in Denver. “If children do not respond to one treatment, parents and providers could consider another option because there is almost a 50% chance of having a better response.”

The multicenter study included 574 participants — about half of whom were ages 5–11 and half 12 years and older. All participants in this study had at least one self-identified African American grandparent, with an average of approximately 80% African ancestry, based on genetic testing.

Of the adolescents over 11 years old and adults, most (49%) responded better to adding a long-lasting bronchodilator than to increasing the inhaled corticosteroid dose, though 20–25% in this group showed no difference in their responses to these approaches.

Investigators also examined whether patient characteristics, including genetic ancestry, could be used to predict the response to the “step-up” treatments in the study participants. But they were unable to use genes indicative of African ancestry, or any of the other patient characteristics they measured in this group of patients, to predict treatment response.

“Although we cannot attribute the study’s findings to genetic markers of African ancestry, there could be as-yet unknown genetic variants specific to people of African descent that affect how severe a patient’s asthma is,” said Wechsler.

Before the trial began, the researchers did not expect the participants to have a better response to treatment regimens that included long-lasting bronchodilators, despite the inclusion of these agents in treatment recommendations. They said they were surprised that many (46% of the young children and 49% of the older children and adults) improved with long-lasting bronchodilators.

“These results provide new data about the management of asthma patients who self-identify as African American regardless of genetic ancestry,” said James Kiley, Ph.D., director of the Division of Lung Diseases at NHLBI. “Every person and their provider should explore all of their management choices to achieve maximum asthma control, based on their response to specific medications.”

About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit https://www.nhlbi.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Protein found in patients with severe asthma can help identify who would benefit from targeted drugs

Novel study establishes that airways periostin is the expression of type 2 endotype severe asthma and helps identify which patients may benefit from newly developed treatments and improved quality of life, report researchers in the journal CHEST®

Glenview, IL, October 22, 2018 – In a novel study, researchers succeeded in identifying patients with a form of severe asthma (type 2 endotype) by measuring periostin concentrations in their airways. These patients with the type 2 (T2) endotype may benefit from newly developed targeted treatments that have the potential to transform their quality of life, report researchers in the journal CHEST®.

Asthma can range from very mild with little or no need for medical treatment to severe and life-threatening. Severe asthma is clinically and biologically varied and identifying the specific type of asthma is crucial in targeting patients who will benefit from new treatment options. The role of periostin, a matricellular protein, in asthma and type 2 inflammatory responses, is an area of active research.

“The T2 immunity severe asthma endotype is one of the most consistent endotypes to emerge probably because it is a key driver in nearly half of all patients with asthma,” explained Giovanna E. Carpagnano, MD, PhD, Institute of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

Investigators analyzed periostin concentrations in the airways of severely asthmatic subjects, evaluating the role of periostin in clustering the T2 endotype. They enrolled 40 consecutive severe asthmatic patients (25 asthmatics of T2 and 15 of non-T2 endotype); 21 patients with mild to moderate asthma; and 15 healthy control subjects. All individuals underwent exhaled breath condensate and sputum collection, eosinophil count in blood, fractional 32 exhaled nitric oxide (FeNO) and immunoglobulin E (IgE) measurement. They found that periostin is measurable in the airways and increased in severe asthmatic subjects, especially in those with the T2 endotype.

“There have been several studies about the value of periostin as a marker of severe eosinophilic asthma, but to measure it in blood limits its value as serum periostin derives from several sources outside the lung and can’t be considered an organ-specific marker,” noted Maria Pia Foschino Barbaro, MD, Institute of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy, who heads the group where the research was conducted.

“Unlike serum periostin, airways periostin is a useful marker of severe eosinophilic asthma and may help to phenotype patients that will respond to the biologic agents,” stated senior investigator Peter J. Barnes, MD, DSc, FCCP, of the Airway Disease Section, National Heart and Lung Institute, Imperial College London, UK. “The newly developed biological treatments have the potential to transform the quality of life of patients with T2 severe asthma. This study suggests that airways periostin is the expression of T2 severe asthma and if validated, could be a useful biomarker to apply stratified medicine for severe asthma, and could transform the quality of life of these patients.”

“Severe uncontrolled asthma is an expensive disease that accounts for more than 60 percent of the costs associated with the disease,” commented Prof. Carpagnano. “The newly developed biological treatments are expensive too, but if directed to the right patients, they will significantly reduce the global cost related to the management of severe asthmatic patients.”

Credit: CHEST®

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Minority Children Failed By Asthma Inhalers: Genomic Analysis Reveals Why

UCSF Highlights Need for More Precision Medicine Research in Underserved Populations

University of California San Francisco researchers report that the largest-ever whole-genome sequencing study of drug response in minority children has revealed new clues about why the front-line asthma drug albuterol does not work as well for African-American and Puerto Rican children as it does for European American or Mexican children.

Asthma is the most common chronic childhood disease in the world, according to World Health Organization estimates. Children with asthma experience difficulty breathing as a result of chronic inflammation of the airways. This inflammation can be alleviated by inhaling drugs called bronchodilators that make the muscles lining the airways relax, allowing them to reopen.

Albuterol is the most commonly prescribed bronchodilator in the world, and often the only medication available to minority children in lower income settings.

Minority Children Respond Least

However, albuterol and other inhaler drugs do not work equally well for all children. In the U.S., Puerto Rican and African-American children – who also have the highest prevalence of asthma nationwide – respond least well to these life-saving drugs.

This may contribute to the four- to fivefold higher rate of death from asthma among these groups, compared to European Americans and Mexicans. Read more of the complete report at UCSF website.

What Researchers Said

“Despite the much higher impact of asthma among African-American and Puerto Rican populations, over 95 percent of studies of lung disease have been performed on people of European descent,” Angel Mak, PhD said. Mak is the UCSF Asthma Collaboratory’s director of genetic research. He was one of the lead authors on the team’s newest study, published in an early online version on March 6, 2018 in the pulmonology journal, American Journal of Respiratory and Critical Care Medicine.

The lab conducted the first large-scale whole genome sequencing study of asthma drug response in African Americans and Latinos. The researchers’ aim was to discover the genetic factors contributing to reduced albuterol response more than was possible in previous association studies.

The test group were a diverse lineup of 1,441 children with asthma who had either very high or very low response to the drug. The genome sequencing was provided courtesy of Trans-Omics for Precision Medicine (TOPMed) Program of the National, Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health.