How Fungi Can Make Asthma Worse and What to Do About It

Hello, dear members and subscribers of the World Asthma Foundation! We hope you are doing well and breathing easy. In this post, we are going to share with you some news about our Defeating Asthma initiative and our continuing series on Severe Asthma.

As you may know, the World Asthma Foundation is a community-based non profit that aims to raise awareness, provide education and support, and advocate for better care and treatment for people living with Asthma. We believe that everyone deserves to breathe freely and enjoy life without the burden of Asthma.

One of our main goals is to shed light on the different types of asthma and how they affect people differently. As most of you already know, Asthma is not a one-size-fits-all condition. It has many subtypes or phenotypes and some yet to be discovered that have different causes, triggers, symptoms, and responses to treatment. Understanding your Asthma phenotype can help you and your doctor find the best management plan for you.

That’s why we continue our focus on Severe Asthma, a challenging form of Asthma that affects about 5-10% of people with Asthma and consumes 80 % of the dollars to treat. Severe Asthma is often difficult to control with standard medications and can have a significant impact on your quality of life, health, and well-being.

One of the possible factors that can contribute to severe asthma is fungi. Fungi are microscopic organisms that are found everywhere in the environment. They can grow on plants, animals, soil, water, food, or indoor surfaces. Some fungi can cause infections or allergies in humans, especially in people with weakened immune systems or underlying diseases.

  • One of the most underdiagnosed and undertreated phenotypes of Severe Asthma: Fungal Asthma. 
  • Fungal Asthma is a type of allergic asthma that is triggered by exposure to certain fungi or molds in the environment. 
  • Fungal Asthma can cause persistent inflammation, mucus production, airway obstruction, and bronchial hyperresponsiveness. 
  • Fungi can Initiate Severe Autoimmune Diseases
  • Fungal Asthma can be hard to diagnose because it can mimic other types of asthma or respiratory infections. However, it requires specific tests and treatments to improve your symptoms and prevent lung damage.

Fungi can affect the lungs and airways of asthmatics in different ways. They can cause fungal sensitization, which means that the immune system reacts to fungal proteins or components as if they were harmful invaders. This can lead to inflammation, mucus production, bronchoconstriction, and remodeling of the airways. Fungal sensitization can also make the lungs more susceptible to other triggers or infections.

Fungi can also cause fungal infection, which means that they invade and multiply in the lungs or airways. This can cause tissue damage, inflammation, and immune activation. Fungal infection can also complicate or mimic other lung diseases, such as tuberculosis or pneumonia.

Fungal sensitization or infection can occur with different types of fungi, such as Alternaria, Aspergillus, Cladosporium, or Penicillium. However, one of the most common and serious forms of fungal involvement in severe asthma is allergic bronchopulmonary aspergillosis (ABPA). ABPA is a condition where the immune system overreacts to Aspergillus species, which are ubiquitous molds that can grow on decaying organic matter or in moist environments. ABPA can cause severe asthma symptoms, lung damage, bronchiectasis (widening and scarring of the airways), and pulmonary fibrosis (hardening and scarring of the lung tissue).

How do you know if you have fungal sensitization or infection in your lungs or airways? Unfortunately, there is no simple or definitive test for this. The diagnosis of fungal sensitization or infection depends on a combination of clinical and immunological criteria, such as:

•  History of exposure to fungi or symptoms suggestive of fungal involvement

•  Skin testing with antigens derived from fungi or measurement of specific IgE levels in the blood

•  Chest imaging (such as X-ray or CT scan) showing signs of lung damage or infection

•  Sputum culture or analysis showing the presence of fungi or fungal components

•  Bronchoscopy (a procedure where a thin tube with a camera is inserted into the airways) showing signs of inflammation or infection

•  Biopsy (a procedure where a small sample of tissue is taken from the lungs) showing signs of inflammation or infection

The treatment of fungal sensitization or infection in severe asthma depends on the type and severity of the condition. The general goals of treatment are to:

•  Reduce the exposure to fungi or eliminate them from the environment

•  Control the asthma symptoms and prevent exacerbations

•  Reduce the inflammation and damage in the lungs and airways

•  Eradicate the fungal infection or reduce its load

The treatment options may include:

•  Asthma medications (such as bronchodilators, corticosteroids, leukotriene modifiers, biologics, etc.) to relieve the symptoms and prevent exacerbations

•  Antifungal medications (such as itraconazole, voriconazole, posaconazole, etc.) to kill or inhibit the growth of fungi

•  Immunotherapy (such as allergen-specific immunotherapy or omalizumab) to reduce the immune response to fungi

•  Surgery (such as lobectomy or pneumonectomy) to remove severely damaged parts of the lungs

The effectiveness and safety of these treatments may vary depending on the individual case and response. Therefore, it is important to consult with your doctor before starting any treatment and follow their instructions carefully.

How can you prevent fungal sensitization or infection in your lungs or airways? There are some measures that you can take to reduce your exposure to fungi or their effects on your health, such as:

•  Avoid or minimize contact with sources of fungi, such as compost, hay, soil, plants, animals, moldy food, or damp places

•  Use a mask, gloves, and protective clothing when handling or working with materials that may contain fungi

•  Clean and dry your home regularly and remove any visible mold or mildew

•  Use a dehumidifier or air conditioner to reduce the humidity and temperature in your home

•  Use a high-efficiency particulate air (HEPA) filter or vacuum cleaner to remove airborne fungi or dust from your home

•  Avoid smoking or exposure to secondhand smoke, as it can damage your lungs and increase your risk of infection

•  Take your asthma medications as prescribed and monitor your symptoms and lung function regularly

•  Seek medical attention promptly if you have any signs or symptoms of fungal sensitization or infection, such as worsening asthma, fever, cough, chest pain, weight loss, or blood in the sputum

Fungi can be a hidden but serious threat for people with severe asthma. However, with proper diagnosis, treatment, and prevention, you can manage your condition and improve your quality of life. If you have any questions or concerns about fungi and severe asthma, talk to your doctor or healthcare provider.

We hope you found this blog post informative and helpful. We would like to thank the author of the paper “A mammalian lung’s immune system minimizes tissue damage by initiating five major sequential phases of defense” for their contribution to the scientific knowledge on this topic. You can read the full paper here: <a href=”″></a>

If you want to learn more about the World Asthma Foundation and our efforts to improve the lives of people with asthma, please visit our website: <a href=””></a>

Thank you for reading and stay tuned for more updates from us!


How Major Fungal Infections Can Initiate Severe Autoimmune Diseases,fungal%20infections%2C%20including%20antibiotic%20usage.

Unraveling the Role of Candidalysins in Severe Asthma

Candida Albicans

Welcome Message from the World Asthma Foundation

Hello to our dedicated community and newcomers alike.

The World Asthma Foundation (WAF) continues its mission to Defeat Asthma by fostering awareness, enhancing education, and promoting research to unravel the complexities of Asthma. We appreciate your interest and partnership as we work towards a world where Asthma is no longer a limiting factor in anyone’s life.

Building on our recent blog post discussing Candida’s role in inflammation and autoimmune response and its implications for severe Asthma, we’re excited to delve deeper into one of Candida’s potent weapons, Candidalysins. This topic is the focus of intensive research globally, including groundbreaking work from the Mayo Clinic, and shows promising potential in understanding the pathogenesis and exacerbation of severe asthma.

Thank you for being part of our mission. We encourage you to share this information with your healthcare provider and engage in open, productive conversations about your health.


Last week, we explored the intricate interplay between Candida colonization, dysbiosis, inflammation, autoimmune responses, TNF-alpha dysregulation, and comorbidities in the pathogenesis and exacerbation of severe asthma. A critical piece of the puzzle involves a protein secreted by Candida, Candidalysins. These proteins play a significant role in Candida’s virulence and are instrumental in driving the inflammatory response, making them a critical research focus in the context of Asthma.

Candidalysins: A Closer Look

Candida albicans produces a group of cytolytic peptide toxins known as Candidalysins, which disrupt host epithelial barriers, leading to infection and promoting inflammation. Recent research indicates that Candidalysins also exacerbate the severity of asthma by enhancing airway inflammation, making the study of these proteins crucial in understanding and managing severe asthma.

The Inflammatory Role of Candidalysins

Candidalysins are known to damage epithelial cells, triggering an inflammatory response. In the context of asthma, this inflammation can intensify symptoms and exacerbate the severity of the condition. Understanding the specific role of Candidalysins in promoting this inflammation can provide insights into new therapeutic strategies for managing severe asthma.

Candidalysins and Immune Response

Research indicates that Candidalysins play a vital role in triggering a strong immune response, affecting immune cell recruitment and activation. This response is critical in the progression of asthma and can provide potential targets for therapeutic intervention.

Implications for Severe Asthma

The role of Candidalysins in promoting inflammation and triggering immune responses has significant implications for severe asthma. Understanding these implications is crucial for developing more effective management strategies, diagnostic tools, and potential treatments.

Candida in Pulmonary Secretions: A New Study

In addition to the role of Candidalysins in severe asthma, we also want to highlight another recent study that may be relevant to our readers. This study, published in The Open Respiratory Medicine Journal, examined the presence and significance of Candida in pulmonary secretions of patients with bronchitis, mucus plugging, and atelectasis. These are conditions that can affect people with asthma and make breathing difficult. The study found that Candida was often associated with these conditions and may play a role in causing or worsening them. The study also found that patients with Candida in their lungs had a higher risk of respiratory failure and death. The study suggested that treating Candida with antifungal drugs may help some patients improve their lung function and outcomes. However, the study was not conclusive and more research is needed to confirm these findings. This study adds to the growing evidence that Candida may be more than just a harmless colonizer of the lungs and may have important implications for severe asthma. You can read more about this study here.


Research into Candidalysins and their role in severe asthma is ongoing and promising. These cytolytic toxins provide a unique perspective on how Candida can influence the severity and progression of asthma, offering potential new avenues for therapeutic intervention. Another recent study also suggests that Candida may affect lung function and outcomes by causing or worsening bronchitis, mucus plugging, and atelectasis in some patients. These findings indicate that Candida may be more than just a harmless colonizer of the lungs and may have important implications for severe asthma. We’re excited to bring you the latest research on this subject and appreciate your interest and involvement in the Defeat Asthma mission. As we continue to unravel the complexities of Asthma, we hope to empower our readers with knowledge and tools to manage this chronic condition.

The Future of Asthma Research

As we understand more about the interactions between the Candidalysins and our body’s immune response, we will continue to see developments in diagnostic tools and therapies. Unraveling this complex relationship is critical in determining the trajectory of severe asthma and holds the key to future breakthroughs in its management.

Your Role in Our Mission

Our readers are a crucial part of our mission to Defeat Asthma. As we continue to share insights from the latest research, we encourage you to keep informed and to share these findings with your network. Conversations about research like this can help increase public understanding of Asthma, combat stigma, and ultimately contribute to better outcomes for those living with Asthma.

What’s Coming Up Next

In our upcoming posts, we will continue to keep you updated on research into the role of Candidalysins and other pathogenic factors contributing to severe asthma. We will also be delving into lifestyle and environmental factors that affect asthma, and how we can manage these to better control this chronic condition.

Stay Tuned for More

Stay connected with us to get the latest information and insights in the world of Asthma research, management, and advocacy. Subscribe to our newsletter, follow us on social media, and share our resources with your community.

Thank You

Thank you for being a part of the World Asthma Foundation community. Your involvement, whether as a reader, donor, advocate, or patient, is critical in our fight to Defeat Asthma. We appreciate your commitment and look forward to a future where Asthma no longer limits anyone’s potential.

How the microbiome affects asthma: new insights from a Spanish study

The World Asthma Foundation (WAF). WAF is a nonprofit organization dedicated to improving the lives of people with asthma through education, research, and advocacy. In this blog post, I want to share with you some exciting findings from a recent study on the microbiome and asthma, published by Spanish researchers in the journal Nutrients.

The microbiome is the collection of microorganisms that live in and on our bodies, such as bacteria, fungi, viruses, and parasites. The microbiome plays an important role in our health and immunity, and can also influence our susceptibility and response to various diseases, including asthma.

Asthma is a chronic inflammatory disease of the airways that affects millions of people worldwide. Asthma can be triggered by different factors, such as allergens, infections, pollution, stress, and diet. Asthma can also have different phenotypes (characteristics), such as allergic or non-allergic, eosinophilic or non-eosinophilic, mild or severe.

What is the microbiome and how does it affect asthma?

The study by Valverde-Molina and García-Marcos reviews the current evidence and challenges on the relationship between the microbiome and asthma, specifically how microbial dysbiosis (an imbalance of the microbial communities in the body) can influence the origins, phenotypes, persistence, and severity of asthma.

How different factors can influence the microbiome and asthma

The study explores how different factors, such as diet, environment, genetics, and infections, can affect the microbiome and asthma, and how modulating the microbiome could be a potential strategy for preventing or treating asthma. The study also reviews the different methods and techniques used to study the microbiome and its interactions with the immune system and the respiratory system.

The gut-lung axis: a key connection between the microbiome and asthma

One of the key points of the study is the importance of the gut-lung axis in the origin and persistence of asthma. The gut-lung axis is the concept that describes how the gut and lung microbiomes communicate with each other through various pathways, such as metabolites, cytokines, antibodies, and immune cells. The gut-lung axis can modulate inflammation and allergic responses in both organs.

The study shows that the process of microbial colonization in the first three years of life is fundamental for health, with the first hundred days of life being critical. Different factors are associated with early microbial dysbiosis, such as caesarean delivery, artificial lactation and antibiotic therapy, among others.

How microbial dysbiosis can lead to different asthma phenotypes and severity

Longitudinal cohort studies on gut and airway microbiome in children have found an association between microbial dysbiosis and asthma at later ages of life. A low ?-diversity (the number of different species) and relative abundance of certain commensal gut bacterial genera in the first year of life are associated with the development of asthma. Gut microbial dysbiosis, with a lower abundance of Phylum Firmicutes (a group of bacteria that includes lactobacilli), could be related with increased risk of asthma.

Upper airway microbial dysbiosis, especially early colonization by Moraxella spp. (a type of bacteria that can cause respiratory infections), is associated with recurrent viral infections and the development of asthma. Moreover, the bacteria in the respiratory system produce metabolites (substances produced by metabolism) that may modify the inception of asthma and its progression.

The role of the lung microbiome in asthma development has yet to be fully elucidated. Nevertheless, the most consistent finding in studies on lung microbiome is
the increased bacterial load (the number of bacteria) and the predominance of proteobacteria (a group of bacteria that includes Haemophilus spp. and Moraxella catarrhalis), especially in severe asthma.

Candida albicans: a fungal culprit in asthma development and exacerbation

The study also mentions Candida albicans (a type of fungus that can cause infections) as one of the fungal genera that can affect the gut and lung microbiome and asthma. Candida albicans can trigger inflammation and autoimmune responses in the body. Candida albicans can also induce a Th17 response (a type of immune response) in the gut and lungs. Candida albicans can also increase lung bacterial load and exacerbate airway inflammation.

This study is very relevant to our own research and findings on Candida’s role in inflammation and autoimmune response: implications for severe asthma. We published an article on this topic on our website on October 13th 2021 which features findings from Mayo Clinic researchers who examined how intestinal fungal microbiota affects lung resident memory CD4+ T cells (a type of immune cell) in patients with asthma.

You can find our article here:

How modulating the microbiome could be a promising strategy for asthma prevention and treatment

We think that these studies complement each other well and provide valuable insights into this important and emerging topic. We believe that understanding the microbiome and its impact on asthma is crucial for developing new and effective strategies for prevention, diagnosis, and treatment of this chronic disease.

Candida’s Role in Inflammation and Autoimmune Response: Implications for Severe Asthma

Welcome Message from the World Asthma Foundation

Hello to our dedicated community and newcomers alike.

At the World Asthma Foundation (WAF), we’re united by a singular, important mission: to Defeat Asthma. Our approach is rooted in fostering awareness, enhancing education, and promoting research that seeks to unravel the complexities of Asthma. As we strive towards a world where Asthma is no longer a limiting factor in anyone’s life, we remain steadfast in bringing you timely, comprehensive, and relevant information.

We’re excited to share our latest blog post with you. This post encapsulates the culmination of the efforts of a variety researchers, clinicians, and organizations worldwide working independently including pioneering work from the Mayo Clinic, to shed light on the pathogenesis and exacerbation of severe asthma.

Mayo Clinic Candida Study

We delve into the compelling evidence pointing towards the intricate interplay between Candida colonization, dysbiosis, inflammation, autoimmune responses, TNF-alpha dysregulation, and comorbidities.

As we unravel these complex relationships, our hope is to equip you, our readers, with knowledge that can empower you in your journey with asthma or help you support someone who is affected.

Let’s continue to learn, share, and work together in our collective fight against Asthma.

Thank you for being a part of our mission. We encourage you to share this information with your healthcare provider.

Establishing a trustworthy and effective relationship with a healthcare provider is crucial to managing your health. It not only ensures that you get the best care but also allows for open and productive conversations about your health.


Managing Severe Asthma remains a complex task for many pulmonary practitioners, despite available medication and trigger avoidance strategies. Frequent attacks and poor symptom control often plague patients. Recent investigations, pieced together by the World Asthma Foundation over time have uncovered dozens of notable research groups that have illuminated the complex relationship between Candida colonization, dysbiosis, inflammation, autoimmune response, TNF-alpha dysregulation, and comorbidities in the pathogenesis and exacerbation of Severe Asthma. This amassed knowledge underscores the multifaceted nature of Severe Asthma, bringing to light the critical role of Candida in the disease process.

Recent studies reveal a potential link between Candida colonization, dysbiosis, inflammation, autoimmune response, TNF-alpha dysregulation, and comorbidities in the pathogenesis and exacerbation of Severe Asthma. This article will provide an overview of these linkages, the financial impact on individuals and society, the necessity for improved diagnostic tools and processes, and source the scientific studies supporting these conclusions.

Candida Colonization, Dysbiosis, and Fungal Sensitization

Candida albicans, a common fungal inhabitant of the mouth, gut, and genital tract, can also colonize the respiratory tract. This colonization is often facilitated by dysbiosis, an imbalance in the normal microbial flora, which can be induced by various factors, including the use of antibiotics and changes in the host immune response. Further, fungal sensitization, a process where the immune system produces antibodies (IgE) against fungal allergens, plays a crucial role in the onset and severity of asthma symptoms. Studies from the Mayo Clinic underline the lower alpha-diversity of lung microbiota and higher fungal burdens in Asthma patients, showing a correlation with severity and poor control of Asthma.

Case in Point

A recent study presented at the CHEST Annual Meeting 2021 by researchers from Mayo Clinic and University of California Davis confirmed the association between intestinal fungal dysbiosis and asthma severity in humans, particularly hospital use in the past year. The study found that patients with asthma who had higher intestinal Candida burden were more likely to have severe asthma exacerbations in the previous year, independent of systemic antibiotic and glucocorticoid use. This suggests that intestinal fungal dysbiosis may worsen asthma control and outcomes in humans. The study also showed that intestinal fungal dysbiosis can enhance the severity of allergic asthma in mice by increasing lung resident group 2 innate lymphoid cells (ILC2) populations, which are important mediators of the gut-lung axis effect. The study used a novel technique of flow cytometry to identify and quantify ILC2 in the lungs of mice. These findings highlight the potential role of intestinal fungal dysbiosis and ILC2 in asthma pathogenesis and management.

Role of Antibiotics and Gut-Lung Axis

Studies show that certain antibiotics prescribed for infections, such as Helicobacter pylori, can lead to gut microbiota dysbiosis, promoting Candida colonization. This gut-lung axis, the communication between gut microbiota and lung health, can create an environment conducive to fungal overgrowth and subsequent infection. As such, understanding this interaction can offer valuable insights into asthma management. Research from the Mayo Clinic suggests that antibiotic usage can significantly contribute to these interactions and, consequently, the pathogenesis of Severe Asthma.

Mechanisms of Candida Colonization

Candida albicans utilizes several mechanisms to cross the intestinal epithelial barrier, including adherence to epithelial cells, invasion, and translocation. Each of these steps facilitates Candida’s ability to invade the host’s system and trigger an immune response. Insights from the Mayo Clinic suggest that bacterial-fungal interactions play a key role in these mechanisms and have implications for Candida colonization.

Candida-Induced Inflammation, Autoimmune Response, and TNF-alpha Dysregulation

Once established, Candida colonization can incite inflammation by provoking the immune system to produce pro-inflammatory cytokines, such as TNF-alpha. While TNF-alpha aids in fighting off infections by initiating inflammation, its dysregulation can lead to chronic inflammation and autoimmune diseases, enhancing the severity of asthma. Research from the Mayo Clinic has shown that Candida colonization in the lung induces an immunologic response, leading to more Severe Asthma.

Autoimmune Response, Comorbidities, and Severe Asthma

Recent studies propose that an autoimmune response could be involved in the onset and exacerbation of Severe Asthma, with TNF-alpha dysregulation playing a pivotal role. Comorbidities like rheumatoid arthritis, often seen in conjunction with Severe Asthma, can further complicate disease management and progression.

Burden, Financial Impact, and Comorbidities

Severe Asthma imposes a substantial burden on individuals and society, financially and otherwise. Healthcare costs, productivity loss, and reduced quality of life contribute to this impact. Asthma comorbidities such as autoimmune diseases can affect disease progression and outcomes, underscoring the need for a comprehensive management approach.

The Necessity for Improved Diagnostic Tools

An accurate diagnosis of Candida colonization, inflammation, and autoimmune response in severe asthma is crucial for optimal patient management. There’s a growing need for improved diagnostic methodologies, tools, and processes. Advances in diagnostic techniques, such as bronchoscopy and bronchoalveolar lavage (BAL), can offer valuable insights into Candida colonization and the associated inflammatory and autoimmune processes. The Mayo Clinic’s recent findings, which identify a unique pattern of lower alpha-diversity and higher fungal burden in the lung microbiota of severe asthma patients, further emphasize the need for enhanced diagnostic methods.


Understanding the link between Candida colonization, dysbiosis, inflammation, autoimmune response, TNF-alpha dysregulation, comorbidities, and severe asthma is crucial for medical practitioners dealing with this chronic disease. The significant burden and financial impacts of Severe Asthma on individuals and society underline the urgency for effective management strategies.

Recognizing the influence of comorbidities, such as autoimmune diseases, can guide comprehensive care plans for patients with Severe Asthma. Moreover, enhanced diagnostic tools and processes will aid in early identification and more personalized treatment approaches, ultimately improving patient outcomes.

By integrating this knowledge, medical practitioners can not only better understand the multifaceted nature of Severe Asthma but also enhance its overall management, leading to improved patient care. With ongoing research, we can continue to unravel the complex relationships and mechanisms in asthma pathogenesis, providing new avenues for therapeutic interventions and improved patient outcomes.

Research on the relationship between Candida albicans and Asthma is an important area of study that could lead to better understanding and management of Asthma. In the following sections, we will present a summary of various significant studies on the relationship between Candida Albicans colonization and asthma. We will also cover information on the microbiome of the gut and lungs, wherever applicable.

Additionally, we will provide key takeaways from each study, including relevant details such as the study’s title, authors, and organization affiliation. Finally, we will summarize the collective findings and scientific conclusions related to Candida Albicans colonization, sensitization, and infection in Asthma, and offer resources for you to share with your healthcare provider.

A comprehensive understanding of these aspects promises to shed light on the intricate mechanisms underlying severe asthma, offering new perspectives in our fight against this chronic condition.

Further Study

Name of study: Fungal Dysbiosis and Its Clinical Implications in Severe Asthma Patients
Date: 2023
Authors: Allison N. Imamura, Hannah K. Drescher, Mai Sasaki, Daniel J. Peaslee, David S. Crockett, Alexander S. Adams, Marcia L. Wills, Stephen C. Meredith, and Andrew H. Limper
Organization: Mayo Clinic, Rochester, MN
Summary: This study discusses the fungal dysbiosis in severe asthma patients. It finds that the lower alpha-diversity of lung microbiota and higher fungal burdens correlate with severity and poor control of asthma. The study also discusses the possible role of antibiotic usage and bacterial-fungal interactions in this process. The study concludes that understanding the link between Candida colonization, inflammation, autoimmune response, and Severe Asthma is crucial for better management of this chronic disease.


•  Date: October 17-20, 202

Authors: Amjad Kanj, Theodore Kottom, Kyle Schaefbauer, Andrew Limper, Joseph Skalski

•  Organization Affiliation: Mayo Clinic and University of California Davis

Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans. Cell 2019. The authors are Petra Bacher, Thordis Hohnstein, Eva Beerbaum, Marie Röcker, Matthew G. Blango, Svenja Kaufmann, Jobst Röhmel, Patience Eschenhagen, Claudia Grehn, Kathrin Seidel, Volker Rickerts, Laura Lozza, Ulrik Stervbo, Mikalai Nienen, Nina Babel, Julia Milleck, Mario Assenmacher, Oliver A. Cornely, Maren Ziegler, Hilmar Wisplinghoff, Guido Heine, Margitta Worm, Britta Siegmund, Jochen Maul, Petra Creutz, Christoph Tabeling, Christoph Ruwwe-Glösenkamp, Leif E. Sander, Christoph Knosalla, Sascha Brunke, Bernhard Hube, Olaf Kniemeyer, Axel A. Brakhage and Carsten Schwarz.
The main objective of the article is to investigate how cross-reactivity against Candida albicans influences human anti-fungal Th17 immunity and pathology.
• C. albicans-specific Th17 cells can cross-react with other fungal antigens and gluten peptides in patients with CeD or asthma.
• Cross-reactive Th17 cells can cause immune pathology in the gut and lung by producing IL-17A and IL-22 cytokines.
Candida and asthma better by showing that Candida can induce a specific type of immune response that can also react to other fungi and allergens that are associated with asthma. The article also suggests that Candida may contribute to the severity and chronicity of asthma by causing inflammation and tissue damage in the lung. mechanisms and consequences of cross-reactivity are complex and need further investigation.

Name of study: Candida auris: Epidemiology, biology, a:Authors:ntifungal resistance, and virulence
Date: 2020
Authors: Du, H., Bing, J., Hu, T., Ennis, C. L., Nobile, C. J., & Huang, G.

Name of study: Candida albicans pathogenicity and epithelial immunity
Date: 2014

Abstract Naglik, J. R., Richardson, J. P., & Moyes, D. L.

Name of study: Candida albicans interactions with the host: crossing the intestinal epithelial barrier
Date: 2019

Abstract: [Unavailable in given data]
Authors: Basmaciyan, L., Bon, F., Paradis, T., Lapaquette, P., & Dalle, F.

Name of study: ACG Clinical Guideline: Treatment of Helicobacter pylori Infection
Date: 2017
Abstract: Authors: Chey WD, Leontiadis GI, Howden CW, Moss SF.

Name of study: Asthma is inversely associated with Helicobacter pylori status in an urban population
Date: 2008

Abstract: [Unavailable in given data]
Authors: Reibman J, Marmor M, Filner J, et al.

Name of resource: H pylori Probiotics: A Comprehensive Overview for Health Practitioners
Date: 2020
Abstract: Authors: Ruscio M.

Name of resource: Treatment regimens for Helicobacter pylori in adults
Date: 2022

Authors: Lamont JT.

Name of study: Effects of probiotics on the recurrence of bacterial vaginosis: a review
Date: 2014
Authors: Homayouni A, Bastani P, Ziyadi S, et al.

Gut Health and Asthma

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.


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, 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).


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).


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).


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.


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.

Gut Health and asthma, an interview with Rodney Dietert, PhD.

See also Dr. Dietert’s interview about the Gut and Lung connection.

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
    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
    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
    Fungal Sensitization
    (Positive Skin Prick Test
    and/or Specific IgE to One or
    More Fungus)
    Other Adult Criteria
    Other Paediatric
    Aspergillus fumigatus
    Cladosporium herbarum
    Penicillium chrysogenum
    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
    IgE < 1000 IgE can be any level
    Negative IgG precipitins to Aspergillus
    IgG precipitins to
    Aspergillus fumigatus
    can be positive or
    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
    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
    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
  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
    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;