World Asthma Foundation is supporting care of Asthma and asthmatics around the world. Please help those that suffer by spreading the word.
The WAF is doing it’s part by:
* Announcing the Defeating Asthma Project with the aim of shining a spotlight on getting to a cure
* Asthma education and advocacy for people with asthma who suffer
World Asthma Day May 5, 2021 Spread the Word
“We can move the needle by taking action now to make the difference for those that suffer from Asthma.” – Alan Gray, Director WAF Australia
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.
In this fifth in a series of interviews with Rodney Dietert PhD, he talks about communication between the gut and lung. Dr. Dietert is Cornell University Professor Emeritus, Health Scientist Head of Translational Science + Education for SEED and the Author of the Human Super-Organism How the Microbiome is Revolutionizing the Pursuit of a Healthy Life we learn about:
* The Gut and lung communication and its relationship to Asthma
World Asthma Foundation “Defeating Asthma Series uncovers New Hope for Asthma Managementant
Asthmatics: Our understanding of Asthma and the way we treat it may soon be radically different from what currently exists, due to new research on the human microbiome and how the microbiome affects asthma.
Interview
World Asthma Foundation: Research into the Microbiome and its relationship to health has improved significantly in the last few years. For example, we now know about the relationship between the gut and health. We’ve also learned about communication between the gut and the lung and the impact on Asthma. Dr. Dietert, so there’s some crosstalk, right?
Video interview: Asthma Connection to Gut and Lung Cross Talk – Rodney Dietert, PhD
Dr. Dietert: Tremendous crosstalk, absolutely tremendous. You’re correct that if you’re looking at endpoints, something like risk of asthma or management of asthma, then you really, at a minimum, are going to focus both on the respiratory system microbiome and the gut microbiome. That’s not necessarily the exclusion of others but those two are really important. Just like the gut microbiome can affect the brain, it can affect behavior, mood. You don’t need lots of hardcore meds as an antidepressant when you’ve got the solution sitting right in your gut in terms of the microbiome.
With the respiratory system, you’ve got both the local microbes being extremely important but you have crosstalk, you have chemical interactions that are originating in the gut that are affecting the respiratory system as well.
World Asthma Foundation: Dr. Dietert, we certainly thank you for your time, all that you do for the microbiome and the community. Good afternoon, and thanks again.
Dr. Dietert: Well, and thank you for all you do with the World Asthma foundation, Bill. Pleasure.
Defeating Asthma Series uncovers New Hope for Asthma Managementant
In this fourth in a series of interviews with Rodney Dietert, PhD Cornell University Professor Emeritus, Health Scientist Head of Translational Science + Education for SEED and the Author of the Human Super-Organism How the Microbiome is Revolutionizing the Pursuit of a Healthy Life we learn about:
* Replacing replacing missing microbes
World Asthma Foundation: Dr. Dietert can we replace missing microbes?
Dr. Dietert: There are products available and we have used a product that is a missing skin microbe. It’s very important in certain metabolic pathways that actually help provide health benefits that are beyond the skin.
Video: Can we replace missing microbes? – Rodney Dietert Ph.D.
That was one that basically was recovered in a very interesting way that involved essentially marriages between some indigenous people and others that were westernized and the microbe being able to not necessarily be removed from a remote location but being able to be a part of what we would call genetically an F1.
There are opportunities to retrieve some missing microbes. I think Dr. Blaser and his wife have done incredible work by the way as well, very much attuned and will have a lot to offer on what’s missing and where is it and can it be retrieved. I think the answer is yes. There are commercial products and we’ve actually used some of them that are the missing microbes.
It’s important to recognize that some of the indigenous peoples that have not had the same environmental experiences that we’ve had, and the same contact with modernization have microbes that are exceptionally important for health are helping prevent obesity and asthma and diabetes in those populations. Those microbes are really the protectors.
Yes, I think that reintroducing those to the extent it is possible is an extremely worthwhile effort.
I would point out that it’s a fragile situation because I think from Dr. Blaser and his wife’s work, you will learn that the indigenous populations in South America if they go into the urban areas, if their children go into the urban areas, start adopting the diet and lifestyle there, it takes no time at all for them to acquire the same set of diseases that we see so prevalent here.
World Asthma Foundation: With that, Dr. Dietert, we certainly thank you for your time, all that you do for the microbiome and the community. Good afternoon, and thanks again.
Dr. Dietert: Well, and thank you for all you do with the World Asthma foundation, Bill. Pleasure.
Among this panel of relatively moderate to severe asthmatics, the respiratory irritants produced by several domestic combustion sources were associated with increased morbidity.
Although there is abundant clinical evidence of asthmatic responses to indoor aeroallergens, the symptomatic impacts of other common indoor air pollutants from gas stoves, fireplaces, and environmental tobacco smoke have been less well characterized. These combustion sources produce a complex mixture of pollutants, many of which are respiratory irritants.
Results of an analysis of associations between indoor pollution and several outcomes of respiratory morbidity in a population of adult asthmatics residing in the U.S. Denver, Colorado, metropolitan area. A panel of 164 asthmatics recorded in a daily diary the occurrence of several respiratory symptoms, nocturnal asthma, medication use, and restrictions in activity, as well as the use of gas stoves, wood stoves, or fireplaces, and exposure to environmental tobacco smoke.
Multiple logistic regression analysis suggests that the indoor sources of combustion have a statistically significant association with exacerbations of asthma. For example, after correcting for repeated measures and autocorrelation, the reported use of a gas stove was associated with moderate or worse shortness of breath (OR, 1.60; 95% CI, 1.11-2.32), moderate or worse cough (OR, 1.71; 95% CI, 0.97-3.01), nocturnal asthma (OR, 1.01; 95% CI, 0.91-1.13), and restrictions in activity (OR, 1.47; 95% CI, 1.0-2.16
The WAF Editorial Board wishes to thank and acknowledge B D Ostro 1 , M J Lipsett, J K Mann, M B Wiener, J Selner
California Environmental Protection Agency, Berkeley for their contribution to Asthma education and research.
The gut and lungs are anatomically distinct, but potential anatomic communications and complex pathways involving their respective microbiota have reinforced the existence of a gut–lung axis (GLA). Compared to the better-studied gut microbiota, the lung microbiota, only considered in recent years, represents a more discreet part of the whole microbiota associated to human hosts. Gut health is not the only area to think about.
While the majority of studies focused on the bacterial component of the microbiota in healthy and pathological conditions, recent works highlighted the contribution of fungal and viral kingdoms at both digestive and respiratory levels. Moreover, growing evidence indicates the key role of inter-kingdom crosstalks in maintaining host homeostasis and in disease evolution.
In fact, the recently emerged GLA concept involves host–microbe as well as microbe–microbe interactions, based both on localized and long-reaching effects. GLA can shape immune responses and interfere with the course of respiratory diseases. In this review, we aim to analyze how the lung and gut microbiota influence each other and may impact on respiratory diseases.
Due to the limited knowledge on the human virobiota, we focused on gut and lung bacteriobiota and mycobiota, with a specific attention on inter-kingdom microbial crosstalk. These are able to shape local or long-reached host responses within the GLA.
Introduction
Recent advances in microbiota explorations have led to an improved knowledge of the communities of commensal microorganisms within the human body. Human skin and mucosal surfaces are associated with rich and complex ecosystems (microbiota) composed of bacteria (bacteriobiota), fungi (mycobiota), viruses (virobiota), phages, archaea, protists, and helminths (Cho and Blaser, 2012).
The role of the gut bacteriobiota in local health homeostasis and diseases is being increasingly investigated, but its long-distance impacts still need to be clarified (Chiu et al., 2017). Among the relevant inter-organ connections, the gut–lung axis (GLA) remains less studied than the gut–brain axis.
So far, microbiota studies mainly focused on the bacterial component, neglecting other microbial kingdoms. However, the understanding of mycobiota involvement in human health and inter-organ connections should not be overlooked (Nguyen et al., 2015; Enaud et al., 2018).
Viruses are also known to be key players in numerous respiratory diseases and to interact with the human immune system, but technical issues still limit the amount of data regarding virobiota (Mitchell and Glanville, 2018). Therefore, we will focus on bacterial and fungal components of the microbiota and their close interactions that are able to shape local or long-reached host responses within the GLA.
While GLA mycobiota also influences chronic gut diseases such as IBD, we will not address this key role in the present review: we aimed at analyzing how lung and gut bacteriobiota and mycobiota influence each other, how they interact with the human immune system, and their role in respiratory diseases.
Gut Health
Microbial Interactions Within the Gut–Lung Axis
The gut microbiota has been the most extensively investigated in gut health. The majority of genes (99%) amplified in human stools are from bacteria, which are as numerous as human cells and comprise 150 distinct bacterial species, belonging mainly to Firmicutes and Bacteroidetes phyla. Proteobacteria, Actinobacteria, Cyanobacteria, and Fusobacteria are also represented in healthy people (Sekirov et al., 2010; Human Microbiome Project Consortium, 2012).
More recently, fungi have been recognized as an integral part of our commensal flora, and their role in health and diseases is increasingly considered (Huffnagle and Noverr, 2013; Huseyin et al., 2017). Fungi are about 100 times larger than bacteria, so even if fungal sequences are 100 to 1,000 times less frequent than bacterial sequences, fungi must not be neglected in the gastrointestinal ecosystem.
Mycobiota Diversity
In contrast with the bacteriobiota, the diversity of the gut mycobiota in healthy subjects is limited to few genera, with a high prevalence of Saccharomyces cerevisiae, Malassezia restricta, and Candida albicans (Nash et al., 2017).
Note from the WAF editorial board. We wish to acknowledge and thank Raphaël Enaud, Renaud Preve, Eleonora Ciarlo, Fabien Beaufils, Gregoire Wieërs, Benoit Guery and Laurence Delhaes for their support of Asthma education and research. For more information about Asthma or Gut Health, visit the World Asthma Foundation.
Although often dichotomized due to technical and analysis sequencing issues, critical interactions exist between bacteriobiota and mycobiota (Peleg et al., 2010). The most appropriate approach to decipher the role of gut microbiota is therefore considering the gut as an ecosystem in which inter-kingdom interactions occur and have major implications as suggested by the significant correlations between the gut bacteriobiota and mycobiota profiles among healthy subjects (Hoffmann et al., 2013).
Yeasts
Yeasts, e.g., Saccharomyces boulardii and C. albicans, or fungus wall components, e.g., ?-glucans, are able to inhibit the growth of some intestinal pathogens (Zhou et al., 2013; Markey et al., 2018). S. boulardii also produces proteases or phosphatases that inactivate the toxins produced by intestinal bacteria such as Clostridium difficile and Escherichia coli (Castagliuolo et al., 1999; Buts et al., 2006).
In addition, at physiological state and during gut microbiota disturbances (e.g., after a course of antibiotics), fungal species may take over the bacterial functions of immune modulation, preventing mucosal tissue damages (Jiang et al., 2017). Vice versa, bacteria can also modulate fungi: fatty acids locally produced by bacteria impact on the phenotype of C. albicans (Noverr and Huffnagle, 2004; Tso et al., 2018).
Microbiota
Beside the widely studied gut microbiota, microbiotas of other sites, including the lungs, are essential for host homeostasis and disease. The lung microbiota is now recognized as a cornerstone in the physiopathology of numerous respiratory diseases (Soret et al., 2019; Vandenborght et al., 2019).
Inter-Kingdom Crosstalk Within the Lung Microbiota
The lung microbiota represents a significantly lower biomass than the gut microbiota: about 10 to 100 bacteria per 1,000 human cells (Sze et al., 2012). Its composition depends on the microbial colonization from the oropharynx and upper respiratory tract through salivary micro-inhalations, on the host elimination abilities (especially coughing and mucociliary clearance), on interactions with the host immune system, and on local conditions for microbial proliferation, such as pH or oxygen concentration (Gleeson et al., 1997; Wilson and Hamilos, 2014).
The predominant bacterial phyla in lungs are the same as in gut, mainly Firmicutes and Bacteroidetes followed by Proteobacteria and Actinobacteria (Charlson et al., 2011). In healthy subjects, the main identified fungi are usually environmental: Ascomycota (Aspergillus, Cladosporium, Eremothecium, and Vanderwaltozyma) and Microsporidia (Systenostrema) (Nguyen et al., 2015; Vandenborght et al., 2019).
In contrast to the intestinal or oral microbiota, data highlighting the interactions between bacteria and fungi in the human respiratory tract are more scattered (Delhaes et al., 2012; Soret et al., 2019). However, data from both in vitro and in vivo studies suggest relevant inter-kingdom crosstalk (Delhaes et al., 2012; Xu and Dongari-Bagtzoglou, 2015; Lof et al., 2017; Soret et al., 2019).
Several Pathways
This dialogue may involve several pathways as physical interaction, quorum-sensing molecules, production of antimicrobial agents, immune response modulation, and nutrient exchange (Peleg et al., 2010). Synergistic interactions have been documented between Candida and Streptococcus, such as stimulation of Streptococcus growth by Candida, increasing biofilm formation, or enhancement of the Candida pathogenicity by Streptococcus (Diaz et al., 2012; Xu et al., 2014).
In vitro studies exhibited an increased growth of Aspergillus fumigatus in presence of Pseudomonas aeruginosa, due to the mold’s ability in to assimilate P. aeruginosa-derived volatile sulfur compounds (Briard et al., 2019; Scott et al., 2019). However, the lung microbiota modulation is not limited to local inter-kingdom crosstalk and also depends on inter-compartment crosstalk between the gut and lungs. Microbial Inter-compartment Crosstalk
From birth throughout the entire life span, a close correlation between the composition of the gut and lung microbiota exists, suggesting a host-wide network (Grier et al., 2018). For instance, modification of newborns’ diet influences the composition of their lung microbiota, and fecal transplantation in rats induces changes in the lung microbiota (Madan et al., 2012; Liu et al., 2017).
Gut-Lung Interaction
The host’s health condition can impact this gut–lung interaction too. In cystic fibrosis (CF) newborns, gut colonizations with Roseburia, Dorea, Coprococcus, Blautia, or Escherichia presaged their respiratory appearance, and their gut and lung abundances are highly correlated over time (Madan et al., 2012). Similarly, the lung microbiota is enriched with gut bacteria, such as Bacteroides spp., after sepsis (Dickson et al., 2016).
Conversely, lung microbiota may affect the gut microbiota composition. In a pre-clinical model, influenza infection triggers an increased proportion of Enterobacteriaceae and decreased abundances of Lactobacilli and Lactococci in the gut (Looft and Allen, 2012). Consistently, lipopolysaccharide (LPS) instillation in the lungs of mice is associated with gut microbiota disturbances (Sze et al., 2014).
Although gastroesophageal content inhalations and sputum swallowing partially explain this inter-organ connection, GLA also involves indirect communications such as host immune modulation.
Gut–Lung Axis Interactions With Human Immune System
Gut microbiota effects on the local immune system have been extensively reviewed (Elson and Alexander, 2015). Briefly, the gut microbiota closely interacts with the mucosal immune system using both pro-inflammatory and regulatory signals (Skelly et al., 2019). It also influences neutrophil responses, modulating their ability to extravasate from blood (Karmarkar and Rock, 2013).
Receptor Signaling
Toll-like receptor (TLR) signaling is essential for microbiota-driven myelopoiesis and exerts a neonatal selection shaping the gut microbiota with long-term consequences (Balmer et al., 2014; Fulde et al., 2018). Moreover, the gut microbiota communicates with and influences immune cells expressing TLR or GPR41/43 by means of microbial associated molecular patterns (MAMPs) or short-chain fatty acids (SCFAs) (Le Poul et al., 2003).
Data focused on the gut mycobiota’s impact on the immune system are sparser. Commensal fungi seem to reinforce bacterial protective benefits on both local and systemic immunity, with a specific role for mannans, a highly conserved fungal wall component. Moreover, fungi are able to produce SCFAs (Baltierra-Trejo et al., 2015; Xiros et al., 2019). Therefore, gut mycobiota perturbations could be as deleterious as bacteriobiota ones (Wheeler et al., 2016; Jiang et al., 2017).
Lung Microbiota and Local Immunity
A crucial role of lung microbiota in the maturation and homeostasis of lung immunity has emerged over the last few years (Dickson et al., 2018). Colonization of the respiratory tract provides essential signals for maturing local immune cells with long-term consequences (Gollwitzer et al., 2014).
Pre-clinical studies confirm the causality between airway microbial colonization and the regulation and maturation of the airways’ immune cells. Germ-free mice exhibit increased local Th2-associated cytokine and IgE production, promoting allergic airway inflammation (Herbst et al., 2011).
Consistently, lung exposure to commensal bacteria reduces Th2-associated cytokine production after an allergen challenge and induces regulatory cells early in life (Russell et al., 2012; Gollwitzer et al., 2014). The establishment of resident memory B cells in lungs also requires encountering lung microbiota local antigens, especially regarding immunity against viruses such as influenza (Allie et al., 2019).
Interactions between lung microbiota and immunity are also a two-way process; a major inflammation in the lungs can morbidly transform the lung microbiota composition (Molyneaux et al., 2013).
Gut Health, Long-Reaching Immune Modulation Within Gut–Lung Axis
Beyond the local immune regulation by the site-specific microbiota, the long-reaching immune impact of gut microbiota is now being recognized, especially on the pulmonary immune system (Chiu et al., 2017).
The mesenteric lymphatic system is an essential pathway between the lungs and the intestine, through which intact bacteria, their fragments, or metabolites (e.g., SCFAs) may translocate across the intestinal barrier, reach the systemic circulation, and modulate the lung immune response (Trompette et al., 2014; Bingula et al., 2017; McAleer and Kolls, 2018).
SCFAs, mainly produced by the bacterial dietary fibers’ fermentation especially in case of a high-fiber diet (HFD), act in the lungs as signaling molecules on resident antigen-presenting cells to attenuate the inflammatory and allergic responses (Anand and Mande, 2018; Cait et al., 2018).
SCFA receptor–deficient mice show increased inflammatory responses in experimental models of asthma (Trompette et al., 2014). Fungi, including A. fumigatus, can also produce SCFAs or create a biofilm enhancing the bacterial production of SCFAs, but on the other hand, bacterial SCFAs can dampen fungal growth (Hynes et al., 2008; Baltierra-Trejo et al., 2015; Xiros et al., 2019). The impact of fungal production of SCFAs on the host has not been assessed so far.
Other Elements
Other important players of this long-reaching immune effect are gut segmented filamentous bacteria (SFBs), a commensal bacteria colonizing the ileum of most animals, including humans, and involved in the modulation of the immune system’s development (Yin et al., 2013). SFBs regulate CD4+ T-cell polarization into the Th17 pathway, which is implicated in the response to pulmonary fungal infections and lung autoimmune manifestations (McAleer et al., 2016; Bradley et al., 2017).
Recently, innate lymphoid cells, involved in tissue repair, have been shown to be recruited from the gut to the lungs in response to inflammatory signals upon IL-25 (Huang et al., 2018). Finally, intestinal TLR activation, required for the NF-?B–dependent pathways of innate immunity and inflammation, is associated with an increased influenza-related lung response in mice (Ichinohe et al., 2011).
Mechanisms
Other mechanisms may be involved in modulating the long-reaching immune response related to gut microbiota, exemplified by the increased number of mononuclear leukocytes and an increased phagocytic and lytic activity after treatment with Bifidobacterium lactis HN019 probiotics (Gill et al., 2001). Diet, especially fiber intake, which increases the systemic level of SCFAs, or probiotics influence the pulmonary immune response and thus impact the progression of respiratory disorders (King et al., 2007; Varraso et al., 2015; Anand and Mande, 2018).
The GLA immune dialogue remains a two-way process. For instance, Salmonella nasal inoculation promotes a Salmonella-specific gut immunization which depends on lung dendritic cells (Ruane et al., 2013). Respiratory influenza infection also modulates the composition of the gut microbiota as stated above. These intestinal microbial disruptions seem to be unrelated to an intestinal tropism of influenza virus but mediated by Th17 cells (Wang et al., 2014).
In summary, GLA results from complex interactions between the different microbial components of both the gut and lung microbiotas combined with local and long-reaching immune effects. All these interactions strongly suggest a major role for the GLA in respiratory diseases, as recently documented in a mice model (Skalski et al., 2018). Gut–Lung Axis in Respiratory Diseases
Acute Infectious Diseases
Regarding influenza infection and the impact of gut and lung microbiota, our knowledge is still fragmentary; human data are not yet available. However, antibiotic treatment causes significantly reduced immune responses against influenza virus in mice (Ichinohe et al., 2011). Conversely, influenza-infected HFD-fed mice exhibit increased survival rates compared to infected controls thanks to an enhanced generation of Ly6c-patrolling monocytes. These monocytes increase the numbers of macrophages that have a limited capacity to produce CXCL1 locally, reducing neutrophil recruitment to the airways and thus tissue damage. In parallel, diet-derived SCFAs boost CD8+ T-cell effector function in HFD-fed mice (Trompette et al., 2018).
Both lung and gut microbiota are essential against bacterial pneumonia. The lung microbiota is able to protect against respiratory infections with Streptococcus pneumoniae and Klebsiella pneumoniae by priming the pulmonary production of granulocyte-macrophage colony-stimulating factor (GM-CSF) via IL-17 and Nod2 stimulation (Brown et al., 2017).
Gut Health and Lung Bacterial Infections
The gut microbiota also plays a crucial role in response to lung bacterial infections. Studies on germ-free mice showed an increased morbidity and mortality during K. pneumoniae, S. pneumoniae, or P. aeruginosa acute lung infection (Fagundes et al., 2012; Fox et al., 2012; Brown et al., 2017). The use of broad-spectrum antibiotic treatments, to disrupt mouse gut microbiota, results in worse outcome in lung infection mouse models (Schuijt et al., 2016; Robak et al., 2018).
Mechanistically, alveolar macrophages from mice deprived of gut microbiota through antibiotic treatment are less responsive to stimulation and show reduced phagocytic capacity (Schuijt et al., 2016). Interestingly, priming of antibiotic-treated animals with TLR agonists restores resistance to pulmonary infections (Fagundes et al., 2012). SFBs appear to be an important gut microbiota component for lung defense against bacterial infection thanks to their capacity to induce the production of the Th17 cytokine, IL-22, and to increase neutrophil counts in the lungs during Staphylococcus aureus pneumonia (Gauguet et al., 2015).
Modulating chronic infectious diseases will similarly depend on gut and lung microbiotas. For instance, Mycobacterium tuberculosis infection severity is correlated with gut microbiota (Namasivayam et al., 2018).
Chronic Respiratory Diseases
Multiple studies have addressed the impact of gut and lung microbiota on chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, and CF (Table 1).
Table 1. Gut–lung axis in human chronic respiratory diseases. Gut Health.
Decreased lung microbiota diversity and Proteobacteria expansion are associated with both COPD severity and exacerbations (Garcia-Nuñez et al., 2014; Wang et al., 2016, 2018; Mayhew et al., 2018). The fact that patients with genetic mannose binding lectin deficiency exhibit a more diverse pulmonary microbiota and a lower risk of exacerbation suggests not only association but also causality (Dicker et al., 2018).
Besides the lung flora, the gut microbiota is involved in exacerbations, as suggested by the increased gastrointestinal permeability in patients admitted for COPD exacerbations (Sprooten et al., 2018). Whatever the permeability’s origin (hypoxemia or pro-inflammatory status), the level of circulating gut microbiota–dependent trimethylamine-N-oxide has been associated with mortality in COPD patients (Ottiger et al., 2018). This association being explained by comorbidities and age, its impact per se is not guaranteed. Further studies are warranted to investigate the role of GLA in COPD and to assess causality.
Early Life Perturbation
Early-life perturbations in fungal and bacterial gut colonization, such as low gut microbial diversity, e.g., after neonatal antibiotic use, are critical to induce childhood asthma development (Abrahamsson et al., 2014; Metsälä et al., 2015; Arrieta et al., 2018).
This microbial disruption is associated with modifications of fecal SCFA levels (Arrieta et al., 2018). Causality has been assessed in murine models. Inoculation of the bacteria absent in the microbiota of asthmatic patients decreases airways inflammation (Arrieta et al., 2015).
Fungi
Furthermore, Bacteroides fragilis seems to play a major role in immune homeostasis, balancing the host systemic Th1/Th2 ratio and therefore conferring protection against allergen-induced airway disorders (Mazmanian et al., 2005; Panzer and Lynch, 2015; Arrieta et al., 2018). Nevertheless, it is still not fully deciphered, as some studies conversely found that an early colonization with Bacteroides, including B. fragilis, could be an early indicator of asthma later in life (Vael et al., 2008).
Regarding fungi, gut fungal overgrowth (after antibiotic administration or a gut colonization protocol with Candida or Wallemia mellicola) increases the occurrence of asthma via IL-13 without any fungal expansion in the lungs (Noverr et al., 2005; Wheeler et al., 2016; Skalski et al., 2018). The prostaglandin E2 produced in the gut by Candida can reach the lungs and promotes lung M2 macrophage polarization and allergic airway inflammation (Kim et al., 2014).
Mouse & Human Gut Health
In mice, a gut overrepresentation of W. mellicola associated with several intestinal microbiome disturbances appears to have long-reaching effects on the pulmonary immune response and severity of asthma, by involving the Th2 pathways, especially IL-13 and to a lesser degree IL-17, goblet cell differentiation, fibroblasts activation, and IgE production by B cells (Skalski et al., 2018).
These results indicate that the GLA, mainly through the gut microbiota, is likely to play a major role in asthma.
Cystic Fibrosis and Gut Health
In CF patients, gut and lung microbiota are distinct from those of healthy subjects, and disease progression is associated with microbiota alterations. (Madan et al., 2012; Stokell et al., 2015; Nielsen et al., 2016). Moreover, the bacterial abundances at both sites are highly correlated and have similar trends over time (Madan et al., 2012). This is especially true regarding Streptococcus, which is found in higher proportion in CF stools, gastric contents, and sputa. (Al-Momani et al., 2016; Nielsen et al., 2016).
Moreover, CF patients with a documented intestinal inflammation exhibit a higher Streptococcus abundance in the gut (Enaud et al., 2019). That suggests the GLA’s involvement in intestinal inflammation. Of note, gut but not lung microbiota alteration is associated with early-life exacerbations. Some gut microbiota perturbations, such as a decrease of Parabacteroides, are predictive of airway colonization with P. aeruginosa (Hoen et al., 2015).
Furthermore, oral administration of probiotics to CF patients leads to a decreased number of exacerbations (Anderson et al., 2016). While the mycobiota has been recently studied in CF (Nguyen et al., 2015; Soret et al., 2019), no data on the role of the fungal component of the GLA are currently available in CF. This deserves to be more widely studied.
Improving Health in the Gut
The role of inter-compartment and inter-kingdom interactions within the GLA in those pulmonary diseases now has to be further confirmed and causality assessed. Diet, probiotics, or more specific modulations could be, in the near future, novel essential tools in therapeutic management of these respiratory diseases.
Conclusion
The gut–lung axis or GLA has emerged as a specific axis with intensive dialogues between the gut and lungs, involving each compartment in a two-way manner, with both microbial and immune interactions (Figure 1). Each kingdom and compartment plays a crucial role in this dialogue, and consequently in host health and diseases. The roles of fungal and viral kingdoms within the GLA still remain to be further investigated. Their manipulation, as for the bacterial component, could pave the way for new approaches in the management of several respiratory diseases such as acute infections, COPD, asthma, and/or CF.
WAF: Gut health is an important area of research for the foundation.
Although non-eosinophilic asthma (NEA) is not the best known and most prevalent asthma phenotype, its importance cannot be underestimated. NEA is characterized by airway inflammation with the absence of eosinophils, subsequent to activation of non-predominant type 2 immunologic pathways. This phenotype, which possibly includes several not well-defined subphenotypes, is defined by an eosinophil count <2% in sputum. NEA has been associated with environmental and/or host factors, such as smoking cigarettes, pollution, work-related agents, infections, and obesity. These risk factors, alone or in conjunction, can activate specific cellular and molecular pathways leading to non-type 2 inflammation.
Note from the WAF: We wish to acknowledge and thank Darío Antolín-Amérigo, Javier Domínguez-Ortega,3,4 and Santiago Quirce Department of Allergy, Hospital General de Villalba, Madrid, Spain, for their contribution to Asthma education and research.
The most relevant clinical trait of NEA is its poor response to standard asthma treatments, especially to inhaled corticosteroids, leading to a higher severity of disease and to difficult-to-control asthma. Indeed, NEA constitutes about 50% of severe asthma cases. Since most current and forthcoming biologic therapies specifically target type 2 asthma phenotypes, such as uncontrolled severe eosinophilic or allergic asthma, there is a dramatic lack of effective treatments for uncontrolled non-type 2 asthma. Research efforts are now focusing on elucidating the phenotypes underlying the non-type 2 asthma, and several studies are being conducted with new drugs and biologics aiming to develop effective strategies for this type of asthma, and various immunologic pathways are being scrutinized to optimize efficacy and to abolish possible adverse effects.
What is aspirin-exacerbated respiratory disease (AERD)
Aspirin-exacerbated respiratory disease (AERD) is a clinical tetrad of nasal polyps, chronic hypertrophic eosinophilic sinusitis, asthma and sensitivity to any medication that inhibits cyclooxygenase-1 (COX-1) enzymes, namely aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) Ingestion of aspirin, and most NSAIDs, results in a spectrum of upper and/or lower respiratory reactions, to include rhinitis, conjunctivitis, laryngospasm and bronchospasm.1,2 AERD affects 0.3-0.9% of the general population, but the prevalence rises to 10-20% of asthmatics and up to 30-40% in those asthmatics with nasal polyposis.3-7 The average age of onset is 34 years in a US study and is thought to be acquired between teenage to middle adulthood years with no ethnic predilection and rare familial associations.3-7 AERD is more commonly reported in females (57% vs. 43%).
Note from the WAF editorial board: The WAF would like to acknowledge and thank Rachel U. Lee1 and Donald D. Stevenson, Division of Allergy, Asthma & Immunology, Naval Medical Center Portsmouth, Portsmouth, VA, USA. and the Division of Allergy, Asthma & Immunology, Scripps Clinic, San Diego, CA, USA for their continued support to Asthma education,.
World Asthma Foundation (WAF) is supporting care of Asthma and asthmatics around the world through a new Severe Asthma Series focused on “Defeating Asthma” with the aim of shining a spotlight on a deeper understanding and getting to a cure.
I’m Alan Gray, the Director of the World Asthma Foundation (WAF) located in Adelaide, Australia. Today, I’m talking to Bill Cullifer, in Northern California, he’s the founder of the World Asthma Foundation (WAF) and a Severe Asthmatic. I’m hoping to spend some socially distanced time with Bill to get his perspective on why he chose to establish the WAF in 2003 and what he finds important about Severe Asthma. We’ll also cover what he’d like me to accomplish heading up the Severe Asthma project as the Director in Australia.
Backstory
Bill retired in 2013 from his Web professional career as a result of battling severe respiratory issues. Complicated by anaphylaxis to Aspirin and allergy to Aspergillus, a common and ubiquitous Fungi in the air we breathe every day. Bill has debilitating Severe Asthma. Severe Asthmatics are at high risk for COVID19, so reaching out to Bill today is timely since he’s isolated like many other Asthmatics. As a colleague and friend, Bill has asked me to lend my web publishing experience to share his 17-year personal journey of discovery with Asthmatics everywhere. I’m pleased to be a supporter of the Asthma community and to lend a hand.
Question and Answer session with Bill Cullifer, Severe Asthmatic and Founder WAF
Alan: Good morning Bill and thanks for making yourself available.
Bill: Good morning Alan and thanks for the kind words and the gracious support. Nice to hear from you today.
Alan: Bill, we’ve known each other for over 20 years dating back to your Web professional efforts to educate and certify Web workers around the globe. I appreciate you reaching out to me to support the Severe WAF and the Severe Asthma Series. To that end, I have a few questions for you.
Bill: Ok, great thanks Alan and thanks for your support.
Alan: Why does Severe Asthma matter to you?
Bill: Great question. Severe Asthma is a global health crisis that affects over 300 million people worldwide. Asthma has already reached Pandemic levels by definition standards published by the World Health Organization (WHO). For those that suffer, Severe Asthma can be very debilitating and can cause premature death. I know first hand because Severe Asthma has dogged me personally for the last 17 years. While inhalers can be effective treatment for some, many Severe Asthmatics require daily systemic steroids, expensive treatment options and physical therapy.
Asthma rates are just getting worse. The projected rate for Asthma tops 400 million worldwide in the middle part of this decade. This is unacceptable really. Despite significant advances in our understanding, Severe Asthma continues to wreak havoc on individuals and our global economy. Given the toll on individuals, the burden on society and the huge financial cost, we need an “all hands on deck” to turn this around. Asthma education and advocacy are an integral piece for solving this puzzling disease in my opinion.
Alan: What can we expect from the WAF Severe Asthma series?
Bill: For a number of Severe Asthmatics, getting to a definitive diagnosis, can take years. In fairness, Severe Asthma is a complex disease, it’s confusing and frustrating for clinicians alike as well.
The Severe Asthma Series is about my own personal journey of discovery. A research journey that’s still unfolding actually. With encouragement from family and friends to share my story with others, I’ve turned over my 17 binders of notes, assembled my documents and medical records. I hope others can benefit from my story.
Alan: Any key takeaways?
Bill: For starters, Asthma is way more complicated than experts first realized actually. Also, Asthma is not a single disease but rather a syndrome. That’s major progress because it’s not only descriptive, it’s the truth. I’ve struggled to understand this for decades. We can’t defeat what we don’t understand and I think that unlocking the mystery is part of the Asthma solution I’d say.
Alan: How are you now and how are you holding up with the global COVID19 pandemic?
Bill: Severe Asthmatics are at high risk for COVID19 according to health experts around the globe. Like many in the over 60 crowd with underlying health issues, I’m hunkering down. I’m trusting my own instincts and following health guidelines by avoiding outside contact by staying indoors and hopefully out of harm’s way. Severe Asthma and COVID19 are both as much mystifying as they are isolating. I empathize with Asthmatics everywhere. It’s really a tough and uncertain time. Playing it smart, I think we’ll get through this.
Alan: Why did you establish the World Asthma Foundation (WAF) and what do you hope to accomplish with the Severe Asthma Series?
Bill: Alan, It’s human nature to want to learn more when you or someone close to you is diagnosed with a potential life threatening illness. To help me improve my personal understanding and diagnosis, I created a simple website at http://worlsasthmafoundation.org in 2003 and registered the WAF on the web. More of a newsfeed really than a website, The goal was to harness and publish daily Asthma news from around the world and to automate the delivery to my email every 24 hours. Community forums were not as robust as they are today. Automation saved me time from manually searching for the daily news. I learn something new about Asthma every day. Way more informational than I ever gleaned from reading the pamphlets at the doctors office. Today, the WAF has evolved to include a lot more than just the news. Over 8k subscribers last I checked. A lot has changed since 2003. Advances in research and technology, along with a number of very passionate researchers is on the rise and its a good thing to be reporting on. Ideally, and if you’re willing, I’m hoping to leverage your web publishing background to provide timely and relevant Asthma information that will benefit those that suffer. Asthma education matters and my hunch is that my findings can go a long way in moving the needle to our collective understanding of Severe Asthma.
Alan: What would you like Asthmatics to know about this series?
Bill: Severe Asthmatics like myself have daily struggles trying to breathe and living to see another day. I’m hopeful that my journey of discovery of the past 17 years will improve the level of understanding for the Asthma community. Asthma for example, is driven by both genetics and environmental factors, We’ve known that for sometime now. But what does that mean exactly? It’s been my mission to unpack this mystery. The genes we inherit are important but what impact does the environment have on our dna? Activation of the immune system has plagued researchers for years and it would also be nice to unpack this mystery as well. To be clear, I’m not a physician, and this should not serve as medical advice. I’m just a regular guy with Severe Asthma that’s trying to figure Severe Asthma out like everyone else. Science is about unlocking the truth and the truth is, together Asthmatics can ultimately prevail in getting the answers to a multitude of questions. Leading to a cure would be fantastic.
Alan: What would you like me to do to help Bill?
Bill: Alan, you’re an experienced web publisher. I’d like you to publish my findings and journey of discovery – a patient perspective to support those that suffer and those that support them. Interview the experts too and support the community with their expertise too. You’re good at this and it will help a lot. I’d be greatly appreciative and I know others will as well.
Alan: Thanks Bill. I appreciate your support as well. Asthma is a worthy cause. Take care of yourself and stay safe!
Bill: Thanks and you as well.
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Harvard Medical School is reporting a couple of days ago on their news its news website, that “What can we learn from people with coronavirus who seek care at outpatient clinics?
NOTE from WAF: We salute Harvard Medical School for the sharing of this research and all of those on the front line. If your an Asthmatic and you experience any of these symptoms including severe shortness of breathe call someone right away.
Since the early days of the COVID-19 pandemic, scientific literature and news reports have dedicated much attention to two groups of patients—those who develop critical disease and require intensive care and those who have silent or minimally symptomatic infections. This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.
Such accounts have mostly overlooked another large and important category of patients—those with symptoms concerning enough to seek care, yet not serious enough to need hospital treatment.
Now, a new analysis by researchers at Harvard Medical School and Harvard-affiliated Cambridge Health Alliance offers insights into this in-between category based on data collected from people presenting at an outpatient COVID-19 clinic in Greater Boston.
The team’s observations, published April 20 in the journal Mayo Clinic Proceedings, are based on data from more than 1,000 patients who visited the clinic for respiratory illness since COVID-19 was declared a pandemic in March.
The findings offer a compilation of clues that can help clinicians distinguish between patients with COVID-19 infections and those with other conditions that may mimic COVID-19 symptoms.
Such clues are critical because early triage and rapid decision-making remain essential even now that testing is becoming more widely available than it was in the early days of the pandemic, the research team said. Testing remains far from universal, and even when available, tests still may have a turnaround time of one to three days. Additionally, some rapid point-of-care tests that have emerged on the market have not been entirely reliable and have caused false-negative readings.
“Early recognition and proper triage are especially important given that in the first days of infection, people infected with SARS-CoV-2 may experience symptoms indistinguishable from a variety of other acute viral and bacterial infections,” said study lead author Pieter Cohen, an associate professor of medicine at Harvard Medical School and a physician at Cambridge Health Alliance. “Even when point-of-care diagnostic tests are available, given the potential for false-negative results, understanding the early natural history of COVID-19 and good old-fashioned clinical skills will remain indispensable for proper care.”
A nuanced understanding of the typical presentation of COVID-19 in the outpatient setting can also help clinicians determine how often to check back with patients, the researchers added. For example, those who have started developing shortness of breath demand very close monitoring and frequent follow-up to check how the shortness of breath is evolving and whether a patient may be deteriorating and may need to go to the hospital.
According to the report, COVID-19 typically presents with symptoms suggestive of viral infection, often with low-grade fever, cough and fatigue, and, less commonly, with gastrointestinal trouble. Shortness of breath usually emerges a few days after initial symptoms, becomes most pronounced upon exertion and may involve sharp drops in blood oxygen levels.
Chief among the team’s findings:
* Fever is not a reliable indicator. If present, it could manifest only with mild elevations in temperature.
* COVID-19 may begin with various permutations of cough without fever, sore throat, diarrhea, abdominal pain, headache, body aches, back pain and fatigue
* It can also present with severe body aches and exhaustion.
* A reliable early hint is loss of the sense of smell in the first days of disease onset.
* In serious COVID-19, shortness of breath is a critical differentiator from other common illnesses.
* Almost no one, however, develops shortness of breath, a cardinal sign of the illness, in the first day or two of disease onset.
* Shortness of breath can appear four or more days after onset of other symptoms.
* The first days after shortness of breath begins are a critical period that requires close and frequent monitoring of patients by telemedicine visits or in-person exams.
* The most critical variable to monitor is how the shortness of breath changes over time. Oxygen saturation levels can also be a valuable clue. Blood oxygen levels can drop precipitously with exertion, even in previously healthy people.
* A small number of people may never develop shortness of breath, but may have other symptoms that could signal low oxygen levels, including dizziness or falling.
* Anxiety—common among worried patients with viral symptoms suggestive of COVID-19—can also induce shortness of breath.
Distinguishing between anxiety-induced shortness of breath and COVID-19-related shortness of breath is critical. There are several ways to tell the two apart.
Key differentiators include:
Time of onset: Anxiety-induced shortness of breath occurs rapidly, seemingly out of the blue, while COVID-19 shortness of breath tends to develop gradually over a few days.
Patient description of sensation: Patients whose shortness of breath is caused by anxiety often describe the sensation occurring during rest or while trying to fall asleep but does not become more pronounced with daily activities. They often describe a sensation of inability to get enough air into their lungs. By contrast, shortness of breath induced by COVID-19-related drops in oxygen gets worse with physical exertion, including performing simple daily activities like walking, climbing stairs or cleaning.
Anxiety-related shortness of breath does not cause drops in blood oxygen levels
During a clinical exam, a commonly used device, the pulse oximeter, can be valuable in distinguishing between the two. The device measures blood oxygen levels and heart rate in a matter of seconds when clipped onto one’s finger.
Several types of pneumonia—a general term denoting infection in the lungs—can present with striking similarity to COVID-19. For example, COVID-19 respiratory symptoms appear to closely mimic symptoms caused by a condition known as pneumocystis pneumonia, a pulmonary infection predominantly affecting the alveoli, the tiny air sacs lining the surface of the lungs. Both COVID-19 patients and patients with pneumocystis pneumonia experience precipitous drops in oxygen levels with exertion and shortness of breath. However, in the case of pneumocystis pneumonia, the shortness of breath typically develops insidiously over weeks, not within days, as is the case with COVID-19. Here, a careful patient history detailing evolution of symptoms would be critical, the authors said.
Likewise, during the initial days of infection, both the flu and COVID-19 may have identical presentations, but thereafter the course of the two infections diverges. People with uncomplicated flu rarely develop significant shortness of breath. When they do experience trouble breathing, the shortness of breath is mild and remains stable. On the rare occasion of when flu causes a viral pneumonia, patients deteriorate rapidly, within the first two to three days. By contrast, patients with COVID-19 don’t begin to develop shortness of breath until several days after they first become ill.
Study co-investigators include Lara Hall, Janice Johns and Alison Rapaport.
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
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.
