David B. Corry, M.D. – Baylor College of Medicine – Fungi in Health & Disease

Air Date: 1-25-2019|Episode 531

This week we welcome Professor of Pathology & Immunology and Medicine, David B. Corry, MD of Baylor College of Medicine, Michael E. Debakey VA Medical Center. We are looking forward to a fascinating discussion on Fungi in Health and Disease with Dr. Corry.

Dr. Corry is a pulmonologist by clinical background and still practices, mostly focusing on allergic airway diseases such as asthma and sinusitis. Most of the time, he is an immunologist and his research focus is into the mechanisms underlying inflammatory lung and other diseases including smoking-related emphysema, asthma, and sinusitis.



Among his groups contributions to science, they have shown how fungi cause allergic inflammation-largely through their release of powerful proteases.  They have further demonstrated the ability of fungi to infect the mouse airway and produce a disease that is essentially identical to asthma and further demonstrated that common human disorders such as asthma and chronic sinusitis are often times, in essence chronic fungal infections. His group primarily relies on antifungal medications to treat their asthma and sinusitis patients. It has been revolutionary and they have published some of their experience, with more to come.

Dr. Corry also recently published a paper on Candida and how it goes directly from the blood stream to the brain in mice. We will also talk about non respiratory health issues and fungi including the state of evidence on Alzheimers, Chronic Fatigue and other health issues sometimes blamed on Fungi. If you are interested in Fungi and Health don’t miss this show.

Z-Man’s Blog:

Fungi in Health & Disease

25 years ago (lung specialist and immunologist) David B. Corry, MD would lose one or two of his patients to asthma annually. He wanted to study asthma so that he could obtain better outcomes. It was known that asthma was inflammatory and patient response was the release of IGE. The environment inhalation pathway was first discovered in Europe where factory workers making powder laundry detergent fortified with protease enzymes to improve stain removal became asthmatics. This remains an ongoing problem. Today he models human inflammatory disease in a lab.

Nuggets mined from today’s episode:

In the Houston area 220 homes were vacuumed and the dust captured examined. While protease was found in all of the homes, fungi was found to be creating the enzyme. Insufficient quantities of protease were found to cause inflammatory disease.

In close proximity to Ear, Nose and Throat surgeons, he was able to obtain samples from patients to culture. Fungi was found in 75% of sinusitis patients and in only 18% of the control group. Fungus directed immune response was found in 95% in fungus patients and not found in the T cell level in control group. This is strong evidence for causation of the disease. In his lab, fungal spores were given to mice and an asthma model using live fungus in mice looks promising, but not published yet. They are currently working on the sinusitis model and

According to Dr. Corry, this is not an association, rather a strong case for causation.

Protease is an enzyme that tears proteins apart. Many living organisms make protease, it helps humans digest food. He has demonstrated the importance of protease in asthma.

Protease for study is inexpensive and readily available. Protease is used in the food industry to ferment soy sauce. The dry powder form of the enzyme is problematic. Soy workers are prone to asthma.

A strain of Aspergillus niger has been genetically engineered not to secrete protease. This strain does not trigger asthma while the strain that secretes protease does.

Opines that aerosolization of protease is the problem. Asian cooking food over high heat creates fine aerosol smoke which is linked to inflammatory reaction. Cooking with MSG has also been linked to inflammatory reaction.

Sinusitis is an inflammatory process. “Paranasal sinuses are a group of four paired air-filled spaces that surround the nasal cavity. The maxillary sinuses are located under the eyes; the frontal sinuses are above the eyes; the ethmoidal sinuses are between the eyes and the sphenoidal sinuses are behind the eyes.” Wikipedia

A percentage of the population lacks frontal sinuses. Irritants are drawn into nasal passages. After inflammation occurs, it gets worse over time. The lining of the sinuses is normally very thin (millimeters, but with inflammation can balloon out to centimeters) thick. Polyps are outpouching of cells which can block airways. Sinuses fill with fluid causing headaches, post sinus drip, cough, altered voice, snoring, etc. Sinusitis is a common co occurrence with asthma.

Allergic inflammation elevates IGE and infection fighting cells. 5%-18% of people presenting have symptoms. People adapt to it. Routine head CT scans done for other reasons commonly show infections.

A revelation. The fungi culturing method used in most hospitals is fundamentally flawed. Fungus colonization is missed because the sample also contains substances designed to kill fungi. The fungi need to be separated from the substances prior to culturing in order for the fungus to grow. Hospitals must change their culture method.

Metagenomic, DNA, microbiome related analysis methods are available for studying infectious fungi.

Biofilm is a matrix of molecules of protein and sugar produced by microorganisms as a protective barrier.

Mucus secreted by airways contains sugar and protein and readily absorbs water and oils.

Treating fungal infections. Several studies of antifungals as primary agents for treating fungal infection are positive, one study was negative. The negative study may have been done differently? A highly effective retrospective study shows that antifungals can be extraordinarily effective and life changing for treating sinusitis/ fungal infections. Eosinophils go down. Some people do not respond to antifungals because their infection is resistant. Treatment takes 6 months-1 year. Pills and aerosols are both used. Aerosol antifungals are potentially more effective and allow stronger doses to get into the airway. In the US aerosol antifungals are not commonly available. Amphotericin b aerosol available in Europe and is commonly used following lung transplants in the US.

Antifungal side effects. Antifungals affect the liver, which is usually reversible. Itraconazole and other agents in this class can cause nerve damage. Antifungals are prescription medications which must be closely monitored.

Antifungal costs. Antifungal medications are very expensive. Insurance companies don’t cover them if given for asthma. They can routinely cost $10Ks per year. Patients may require them for life.

Chronic fungal infection can persist in our bodies for decades and produce difficult to treat chronic illness such as asthma and sinusitis. Whether or not they contribute to other disorders such as chronic fatigue, arthritis, and atherosclerosis is an open question.

What is the fundamental underlying cause of diseases, is there a fungal link? Arthritis, rheumatoid arthritis (an immune disease), osteoarthritis, hypertension, vascular inflammation, heart disease, Alzheimer’s, dementia, etc.- we do not yet know what causes these disorders at a fundamental level

Fungi has been found in plaque removed from arteries.

Asthma has been linked to late onset Alzheimer’s and dementia. Spanish pathologists found yeast and fungi in the brains of all 10 brains with late onset Alzheimer’s and dementia studied and none in healthy brains.

Survivors of hospital acquired bloodstream infections previously thought to be bacteria related now may be fungal. These survivors soon battle dementia or Alzheimer’s. Candida bloodstream infections can produce a pattern of brain injury that is strikingly similar to that seen in Alzheimer’s.

Mold infections in lungs can spread to the brain in persons with profound defects in their immune systems

Life threatening asthma and sinusitis are likely manifestations of a form of immune deficiency making them more vulnerable to fungal infections. This may affect 1% of the US population as a genetically based immune problem.

Bacterial biofilms may provide protection against fungi. Hand sanitizers should be used in hospitals. Hand sanitizers might, along with the overuse of conventional antibiotics, wreck the human microbiome and make it easier for fungi to set up chronic infections, leading to disorders such as asthma and sinusitis.

Final comment:

Political activism, we need a political solution.

Follow up Question from a listener and answer from Dr. Corry

Question: Joe–great program. I have a question: is there any way to prevent fungal infections (besides not growing mold indoors)?

Answer: Because fungi, unlike for example the organisms that cause TB, anthrax, influenza and most others, are ubiquitous and we breathe their infective spores with every breath whether indoors or outdoors, it is impossible to prevent fungal infections.  All humans-no exceptions-are infected with fungi from day 1 of birth to our last breath.  So, the key is not preventing infection-that is impossible-the key is to prevent serious fungal-related disease.

Part of this is keeping our exposure to fungi to an absolute minimum-and that means keeping the built environment scrupulously clean of fungi.  Most of us recognize the importance of general cleanliness and excluding mold from our homes and work spaces; not well recognized today is the need to take care of our internal environments to reduce to the absolute minimum the possibility of our inevitable minor fungal infections blossoming into serious issues.  In part, taking care of our internal environments means the following:

-not taking conventional antibiotics unless absolutely necessary and even then, for the shortest possible time

-not taking immunosuppressive medications (e.g., steroids, modern therapies for autoimmune disorders such as rheumatoid arthritis, etc.) unless absolutely necessary and even then, for the shortest possible time

-Not taking agents that suppress stomach acid production unless absolutely necessary and even then, for the shortest possible time.

-managing effectively medical conditions that increase our risk of serious fungal infections. There are many of these; some of the biggies include AIDS, diabetes, and liver failure.

Z-Man signing off

Trivia Question

Name the two primary pathogenic fungal infection risks found in bird and bat droppings?

Answer:

Histoplasmosis and Cryptococcus

Answered by: Andrew Gondzur, Certified Safety Consultants, St. Louis, MO

Some Key points from papers by Dr. Corry and his team:

Airway surface mycosis in chronic TH2-associated airway disease

Background: Environmental fungi have been linked to TH2 cell-related airway inflammation and the TH2-associated chronic airway diseases asthma, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown. Objective: To determine the frequency of fungus isolation and fungus-specific immunity in patients with TH2-associated and non-TH2-associated airway disease.

Conclusions: The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with TH2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients.

Chronic rhinosinusitis (CRS) is an inflammatory process of the nasal and paranasal sinus mucosa that affects more than 30 million people annually and results in more than $6 billion in direct health care costs.1 Chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are associated with TH1- and TH2-associated cytokine responses, respectively.2,3 Many studies have implicated infectious agents including fungi, bacteria, and viruses in the pathogenesis of CRS, but the precise relationship of infectious agents with the expression of TH2-associated diseases is not known.4-6

Proteinases as molecular adjuvants in allergic airway disease

General significance: Clarification of how proteinases cause allergic disease, specifically confirming an infectious basis for airway proteinase exposure, will likely radically advance how asthma and related respiratory tract disorders are diagnosed and treated.

Cleavage of Fibrinogen by Proteinases Elicits Allergic Responses Through Toll-Like Receptor 4

Proteinases and the innate immune receptor Toll-like receptor 4 (TLR4) are essential for expression of allergic inflammation and diseases such as asthma. A mechanism that links these inflammatory mediators is essential for explaining the fundamental basis of allergic disease but has been elusive. Here, we demonstrate that TLR4 is activated by airway proteinase activity to initiate both allergic airway disease and antifungal immunity.

Thus, allergic airway inflammation represents an antifungal defensive strategy that is driven by fibrinogen cleavage and TLR4 activation. These findings clarify the molecular basis of allergic disease and suggest new therapeutic strategies.

Benefits of antifungal therapy in asthma patients with airway mycosis: A retrospective cohort analysis

Introduction:Fungal airway infection (airway mycosis) is increasingly recognized as a cause of asthma and related disorders. However, prior controlled studies of patients treated with antifungal antibiotics have produced conflicting results. Our objective is to measure the effect of antifungal therapy in moderate to severe adult asthmatics with positive fungal sputum cultures in a single center referral-based academic practice.

Methods:We retrospectively evaluated 41 patients with asthma and cultureproven

airway mycosis treated with either terbinafine, fluconazole, itraconazole, voriconazole, or posaconazole for 4 to >12 weeks together with standard bronchodilator and anti-inflammatory agents. Asthma control (1¼very poorly controlled; 2¼not well controlled; and 3¼well controlled), peak expiratory flow rates (PEFR), serum total IgE, and absolute blood eosinophil counts before and after antifungal therapy were assessed. In comparison, we also studied nine patients with airway mycosis and moderate to severe asthma who received standard therapy but no antifungals.

Results:Treatment with azole-based and allylamine antifungals was associated

with improved asthma control (mean change in asthma control 1.72-2.25; p¼0.004), increased PEFR (69.4% predicted to 79.3% predicted, p¼0.0011) and markedly reduced serum IgE levels (1,075 kU/L to 463 kU/L, p¼0.0005) and blood eosinophil counts (Mean absolute count 530-275, p¼0.0095). Reduction in symptoms, medication use, and relapse rates decreased as duration of therapy increased. Asthmatics on standard therapy who did not receive antifungals showed no improvement in asthma symptoms or PEFR. Antifungals were usually well tolerated, but discontinuation (12.2%) and relapse (50%) rates were relatively high.

Conclusion: Antifungals help control symptoms in a subset of asthmatics with culture-proven airway mycosis. Additional randomized clinical trials are warranted to extend and validate these findings.

Microglia and amyloid precursor protein coordinate control of transient Candidacerebritis with memory deficits

Bloodborne infections with Candida albicans are an increasingly recognized complication of modern medicine. Here, we present a mouse model of low-grade candidemia to determine the effect of disseminated infection on cerebral function and relevant immune determinants. We show that intravenous injection of 25.000 C. albicans cells causes a highly localized cerebritis marked by the accumulation of activated microglial and astroglial cells around yeast aggregates, forming fungal-induced glial granulomas. Amyloid precursor protein accumulates within the periphery of these granulomas, while cleaved amyloid beta (Aβ) peptides accumulate around the yeast cells. CNS-localized C. albicans further activate the transcription factor NF-κB and induce production of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor (TNF), and Aβ peptides enhance both phagocytic and antifungal activity from BV-2 cells. Mice infected with C. albicans display mild memory impairment that resolves with fungal clearance. Our results warrant additional studies to understand the effect of chronic cerebritis on cognitive and immune function.

Diverse environmental fungi are increasingly recognized as causal or contributory to the majority of common chronic, cutaneous inflammatory conditions such as atopic dermatitis (eczema), onychomycosis, and common mucosal inflammatory conditions such as pharyngitis/laryngitis, esophagitis, asthma, chronic rhinosinusitis, vaginosis, and colitis1. Cutaneous candidal disease in the form of mucocutanous candidiasis assumes a much more invasive and destructive character in the context of immunodeficiencies1,2. Fungi are further implicated in diseases as diverse as rheumatoid arthritis3 and Alzheimer’s disease (AD)4,5,6,7,8.

In addition to their frequent involvement in mucosal and cutaneous diseases, the fungi are further emerging as major causes of invasive human diseases such as sepsis, especially in intensive care units in the context of critical illness. Candidemia and fully invasive candidiasis, mainly caused by Candida albicans and related species9,10, is an especially serious concern in the nosocomial setting where it has emerged as one of the leading bloodstream infections in developed countries, producing high mortality and costing >1 billion dollars annually in the United States alone11. Diagnosis of candidemia can be difficult, as clinical signs and symptoms are often protean and non-specific, often presenting late in the course of infection when therapy is much less likely to be effective12. Moreover, blood fungal cultures and fungal-based serodiagnostic approaches lack sensitivity. Thus, a better understanding of fungal, especially candidal, disease pathogenesis, diagnosis, and therapy is emerging as an essential medical challenge of the 21st century.

Unique inflammatory responses have evolved to combat fungi growing along epithelial surfaces. Careful dissection of mucosal allergic inflammatory responses has revealed that characteristic granulocytes (eosinophils), cytokines (interleukin (IL)-5 and IL-13), and T effector cells (T helper type 2 (Th2) cells; Th17 cells) are potently fungicidal or at least are required for optimal fungal clearance at mucosal sites in vivo13,14.

Radio Joe Comments:

We have had numerous shows with MD’s discussing mold and health. They have all been excellent but this one was particularly interesting to me and should be of interest to all practitioners. We continue to unravel the mysteries of Mold and Health. Thanks David!

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