Understanding Mold Related Illnesses

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Understanding Mold Related Illnesses

• University of North Texas Health Science Center
  in Fort Worth
• Stevan Cordas DO MPH
• Occupational, Allergic and Environmental Medicine.

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Molds! An Overview

• Molds are non chlorophyll containing filamentous,
  spore producing organisms containing chitin in
  cell walls instead of cellulose and lignin and
  ergosterol instead of cholesterol.
• Of over 100,000 types, about 300 are pathogenic
  to man.
• Four types of disease Hypersensitivity,
  mycotoxicosis, mycetismus and infection.

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Mycotoxicoses

• The big scary thing
• Example Ergotism
• Claviceps purpurea
• Infects rye
• Produces sclerotia
• Ergot is released
• Huge outbreaks
• Salem witch trials?
• Image from www.TomVolkFungi.Net

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Classification of Pathogenic Molds

• Actinomycetes Nocardiosis, Streptomycetes
  mycetoma, Lumpy jaw- These are really bacteria.
• Yeasts Candidiasis, Cryptococcosis.
• Superficial mycosis Tinea.
• Filamentous fungi- Aspergillosis,
  Chromoblastomycosis.
• Dimorphic fungi Histoplasmosis,
  Coccidiomycosis, Blastomycosis.

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Lumpy Jaw from Actinomycetes isreali
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Diagnosis

• Skin scrapings KOH.
• Skin testing except for allergy testing not
  commonly used - i.e. Histo and Coccidio testing.
• Serology Latex agglutination IgM, double
  immunodiffusion and Complement fixation, ELISA-
  IgG.
• Direct fluorescent microscopy.

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Diagnosis

• Biopsy and histopathology Gomori methenamine
  silver stain.
• Culture Sabouraud dextrose agar pH 5.6. two
  samples cultured at 37 C and 25 C to check for
  dimorphism.
• Immunological and other methods to examine
  mycologic byproducts endotoxins, mycotoxins
  just emerging.

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The Known and the Unknown

• Many molds appear not to be human pathogens. Some
  are beneficial PCN and other antibiotics, ergot,
  cyclosporin etc.
• Some mold problems are clearly defined and well
  understood.
• These include various manifestations of
  Aspergillosis and Candidiasis.
• No review of mold pathogens would be complete
  without at least some overview of these pathogens.

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Candida From a Skin Lesion
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Candida Species

• Most common form of mycotic disease in man. About
  200 species. Do not call them Moniliasis.
  Torulopsis species are now added to the genus
  Candida.
• They are differentiated mainly by fermentation
  characteristics and morphology in the laboratory .

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Candida Species

• These are asexual imperfect yeasts (Division
  Fungi Imperfecti).
• May produce budding (blastoconidia), pseudohypae
  or actual mycelium. The latter is usually
  affiliated with invasiveness.
• Some forms are drug resistant.
• Ex C. glabrata, tropicalis, krusei, lusitaniae.
• Infections can be superficial, local, or
  systemic.
• Recurring yeast infections defective CMI.

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Candida Species

• Candida is the leading cause of opportunistic
  infections. Candida albicans is the most common
  pathogenic species.
• They can affect nipples when breastfeeding, mouth
  (thrush), vagina, skin and nails (onchomycosis),
  brain (abscess and meningitis), gastrointestinal
  tract esophageal, pharyngeal, intestinal,
  cystitis and pyelonephritis, endocarditis, liver,
  spleen and lung including fungus ball.

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Penile Candida
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Cutaneous Candida
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Cerebral Candidiasis
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Aspergillosis

• 900 species of Aspergillus. 75 of human
  infection caused by A. fumigatus. A. flavus next
  most common and more likely to disseminate.
  Usually these molds found in neutropenic or
  immunocompromised hosts (esp. HIV).
• Even large amounts normally wont bother a
  normal person.
• May cause 3 types of problems. Allergic
  Localized - Invasive.

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A. Flavus Conidia
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Different Types of Allergic Patterns to
Aspergillus

• The conidia of Aspergillus can precipitate
  bronchial asthma.
• Allergic rhinitis.
• Allergic sinusitis.

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Different Types of Allergic Patterns to
Aspergillus

• Allergic bronchopulmonary aspergillosis (ABA)
  Transient atelectatic lines on x ray, fever,
  eosinophilia sputum, blood. More persistent
  bronchial obstruction.
• Extrinisic allergic bronchiolitis (EAB) - A.
  clavatus 4 hours after breathing malt or grain.
  Repeated bouts can lead to pulmonary fibrosis.

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Invasive Aspergillosis in HIV
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Granulomatous Response and Mycelia of A.
Fumigatus.
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Aspergillus of the Skin
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Aspergillus in the Human Mouth
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Treatment of Various Aspergillus Infections.

• ABA Corticosteroids.
• EAB Same avoid moldy grains.
• Invasive liposomal Amphotericin B, regular
  Amphotericin B or itraconazole.
• Aspergilloma Removal if massive hemoptysis
  occurs only.
• Resection with Sino naso orbital type is
  required. Usually A. flavus.

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Molds and Indoor Contamination

• Black molds are causing the closing of schools,
  businesses, firehouses, apartments and entire
  buildings.
• Some toxigenic molds are not black.
• Some black molds are not Stachybotrys.
• Much hysteria.
• Some fact.

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Molds

• Separate kingdom Neither plant or animal.
• Indoor molds include Cladosporium,Penicillium,
  Aspergillus, Alternaria, Wallenia, Chaetomium,
  Acremonium and less commonly Stachybotrys
  chartarum (the famous black mold).

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Products From Molds

• Allergens
• Endotoxins,
• 1-3 B-D- Glucans
• Mycotoxins
• Ergosterols
• Extracellular Polysaccharides
• VOC
• Enzymes

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Exposures From Work or Schools

• Of 131.2 Million workers in the US, 70 Million
  work indoors. OSHA reported that 30 of those
  indoors are subjected to poor air quality.
• NIOSH reported that of 104 buildings
  investigated, 42 had water damage.
• 1/2 of our 115,000 schools in the US have a
  problem with indoor air quality. 55 million
  children affected. (EPA).

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EPA

• The Indoor Air Quality (IAQ) Tools for Schools
  Kit (Kit) shows schools how to carry out a
  practical plan of action to improve indoor air
  problems at little or no cost using
  straightforward activities and in-house staff. 
  Indoor Air Quality Tools for Schools is
  co-sponsored by the National PTA, National
  Education Association, Council for American
  Private Education, Association of School Business
  Officials, American Federation of Teachers, and
  the American Lung Association.

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Exposure From Homes

• US Census 1998 indicates that 13 or 10.9 million
  US homes had water damage from inside.
• 16.9 million or 21 of US homes had leakage from
  outside.

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Potential Indoor Agents

• Fungal products
• Bacteria and their endotoxins
• Viruses
• Volatile Organic Compounds
• Other Materials outgassing
• Heavy metals (mercury)

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Clinical Observations

• The presence of mold as observed or bulk sampling
  does not correlate with clinical symptoms well.
  There must be the presence of spores, fragments
  or metabolites in the air or direct contact or
  ingestion of the material to make problems.
• Problems develop and vary with atopic status,
  age, state of health and concurrent exposures.
  COPD and allergic individuals more prone.

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Allergic Statistics

• 50 Million allergic rhinitis cases in US.
• 17.3 Million asthmatics in the US (CDC).
• Expected to double by 2020.
• 15 of asthmatics are reported to be from
  occupational causes.
• 450 Substances in the workplace that can cause
  occupational asthma.
• Molds are the second most common allergy in the
  US after dust mites.

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Molds Known to Cause Allergies

• Absidia
• Agaricus
• Alternaria
• Amillaria
• Aspergillus
• Aureobasidium
• Botrytis
• Candida

• Cantharelius
• Chaetomium
• Chlorophyllum
• Cladosporium
• Claviceps
• Coniosporium
• Coprinus
• Curvularia

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Molds Known to Cause Allergies

• Dacrymyces
• Daldinia
• Epicoccum
• Epidermophyton
• Erysiphe
• Eurotum
• Fuligo
• Fusarium

• Ganoderma
• Gliocladium
• Helminthosporiu
• Hypholoma
• Lycogala
• Monilia
• Mucor
• Nigrospora

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Molds Known to Cause Allergies

• Paecilomyces
• Penicillium
• Phoma
• Pleurotus
• Podaxis
• Polyporus
• Puccinia
• Rhizopus

• Rhodotorula
• Saccharomyces
• Serpula
• Sporobolomyces
• Sporotricium
• Stachylidius
• Stemonitis
• Stemphylitis

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Molds Known to Cause Allergies

• Stereum
• Tillelia
• Trichoderm
• Trichothec
• Urocystis
• Usilago
• Xylaria

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Fungal Sinusitis

• Allergic fungal sinusitis
• Chronic invasive fungal sinusitis
• Indolent granulomatous fungal sinusitis
• Fungal ball (mycetoma)
• Acute invasive fungal sinusitis

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Bipolaris Spicifera
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Clinical Observations

• A number of investigators are observing patients
  that are not allergic but have similar symptoms -
  Irritative and neurologic.
• In most cases, the symptoms persist as long as
  they are in the moldy environment and get better
  eventually if they leave it.
• We are interested in investigating and helping
  those cases that dont seem to improve on their
  own.

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Animal Mycotoxicosis

• Well known to vets and grain handlers.
• Causes corn poisoning in horses
  (leukoencephalopahty) fumonisin. FDA guidance.
• Deoxynivalenol (DON) is a vomitotoxin in man and
  animals. Cold wet Pigs affected most wheat
  contamination. Common.
• Zearalenone produces feminization of animals and
  interferes with reproduction.

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Mycotoxins

• Over 400 now identified.
• 5 types Ochratoxins (nephrotoxic), Rubratoxins,
  Fumonisins (produce many harmful types),
  Aflatoxins (the most carcinogenic natural
  substance known), and trichothecenes (3 classes).
• One fumonisin was weaponized T2.
• Orenberg, Siberia 1943 Alimentary toxic aleukia
  (ATA).

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Main Mycotoxin generating molds
Aspergillus flavus, Emericella (Aspergillus)
nidulans, Penicillium expansum, Aspergillus
fumigatus, Paecilomyces variotii, Penicillium
italicum, Aspergillus niger, Penicillium
aurantiogriseum, Penicillium roqueforti,
Aspergillus ochraceus ,Penicillium
brevicompactum, Penicillium viridicatum,
Aspergillus parasiticus, Penicillium chrysogenum,
Stachybotrys chartarum, Aspergillus ustus,
Penicillium citrinum, Trichoderma harzianum,
Aspergillus versicolor, Penicillium corylophilum
,Trichoderma viride, Chaetomium globosum,
Penicillium digitatum, various Fusarium.
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T2
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T2 As a Weapon

• Only biological agent that can kill through
  intact skin.
• Some evidence that it killed villagers in
  Afghanistan, Laos and Kampuchea.
• Produces intense burning and skin necrosis,
  pulmonary edema, multisystem disease resembling
  radiation poisoning.
• Sadam, aflatoxin and the Scud missiles. The
  future?

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Clinical Observations -Controversy

• The role of mycotoxins creating illness, other
  than allergies, from those molds found in homes
  and schools is controversial.

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Clinical Observations -Controversy

• Case reports and cross sectional studies
  primarily. Case controls starting to appear. CDC
  1993 Cleveland cohort. Can not conclusively prove
  causation.
• Ann Allergy Asthma Immunol 2001 Dec87(6 Suppl
  3)57-63. There is a failure to establish, after
  a review of the literature, that human disease
  can be attributable to Stachybotrys even in water
  damaged buildings. An exception may be pulmonary
  hemosiderosis/hemorrhage in children.

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CDC

• Cluster of infants in Cleveland with Pulmonary
  hemorrhage and hemorrhage. 47 cases 6 deaths
  1993-1996. First 10 cases studied 1993 by CDC.
  Stachy found in some homes and also in homes of
  controls without symptoms. Tobacco smoke
  incriminated. Was Stachy a cofactor?
• June 17 1999 Update report by CDC- No
  conclusion that it was.

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Some References Supporting Toxigenic Molds and
Illness.

• Sudakin DL. AJIM 1998 August 34(2)184-190
• Etzel RA. JAMA 2002 Jan 23-30 287(4) 425-7 (Good
  review)
• Johanning E, Landsbergis P. Clinical findings
  related to indoor fungal exposure review of
  clinical data of a specialty clinic in
  Bioaerosols, Fungi and Mycotoxins Health
  Effects, Assessment, Prevention and Control.
  Johanning E. ed. Mount Sinai School of Medicine,
  Department of Community Medicine, Fungal Research
  Group (2001) Fungal Research Group

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World Health Organization

• The World Health Organization states, the
  mycotoxins described in their treatise, are
  acutely toxic, carcinogenic, immunosuppressive
  and oestrogenic and have been the cause of
  serious human and/or animal diseases. The
  potential immunosuppressive role of mycotoxins in
  the aetiology of human disease is an especially
  important issue, which requires further careful
  study.

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World Health Organization Contd.

• Every effort must be made to minimize the
  occurrence of mycotoxins in food and feed grains.
  Undoubtedly, the implementation of improved
  handling and quality control procedures will have
  a significant effect on the incidence of
  mycotoxins in important foods and feeds
  throughout the world.

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Other Reviews Different Opinions.

• Health Implications of Fungi in Indoor
  Environments. RA Samson, B. Flannigan, et al eds.
  Elsevier Science BV, Amsterdam, the Netherlands,
  1994.
• We have known for years that aflatoxin, a
  mycotoxin produced by Aspergillus flavus, is a
  Class 1 carcinogen. Aflatoxin in association with
  Hepatitis B is responsible for many thousands of
  deaths per year., This probably also includes
  Hepatitis C.

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Other Reviews Different Opinions

• Other suspected carcinogenic mycotoxins include
  Ochratoxin A (urinary tract cancers and kidney
  disorders in Eastern and Northern Europe),
  zearalenone, which produce estrogenic effects in
  man and animals, fumonisins which appear to be
  associated with esophageal cancer in parts of
  China and Africa Fumonisins have been implicated
  in cases of anencephaly along the Rio Grande in
  Texas. They block folate.

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Other Reviews Different Opinions

• Trichothecenes of various types are generally
  immunosupressives and may have neurotoxic or
  hemolysin properties. Fungal byproducts are also
  teratogenic, and mutagenic and can influence the
  reproductive cycle of animals and possibly man.
  Much research in this area is still required.
  Other illnesses related to molds are mold related
  sinusitis, Farmers lung, organic toxic dust
  syndrome, hypersensitivity pneumonitis,
  occupational rhinitis and asthma, and building
  related illness. .

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Clinical Observations

• Evidence leans toward mycotic byproducts being
  contributory to human illness in some cases with
  high exposure or genetic susceptibility.
• Many fungi can make mycotoxins including
  Tricoderma, Menmoniella, Aspergillus, Fusarium,
  and Penicillium in addition to S. chartarum.

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Stachybotrys Chartarum

• Uses cellulose as its carbon source (wall board,
  sheet rock (gypsum), paper, ceiling tile).
• Not very allergenic.
• Implicated in infant Hemosiderosis and hemorrhage
  (CDC).
• 15 strains not all produce mycotoxins.
• Depends on the strain and moisture.
• Can infest grains that are moist, barns.
• Causes Stachybotrytoxicosis.

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Mycotoxins

• Stachybotrys produces a number of trichothecene
  mycotoxins that inhibit DNA and other protein
  metabolism, Reduce immune responses and cause
  cell apoptosis. There are 15 species of this
  mold.
• The mycotoxins are Satratoxins, Roridin,
  lactams, Isosatratoxin, Verrucarin, Epiisororidin
  and Trichoverrol B.

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Cognitive Impairment Associated With Exposure to
Toxigenic Fungi

• Gordan et al at Mt Sinai School of Medicine have
  shown that 13 out of 20 subjects tested with
  neuropsychological batteries, who were exposed to
  Stachybotrus, have cognitive impairment. This was
  especially in verbal learning, attention/concentra
  tion, set shifting. Also this group had a higher
  number of physical and behavioral symptoms.

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Encephalopathy

• Auger and his team report several cases of toxic
  encephalopathy apparently from neurotoxins from
  indoor molds.
• Auger PL, Gordeau P et al 1. 1998 AJIM 25(1)
  41-42.

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Other Molds of Concern and Their Mycotoxins.

• Aspergillus flavus Kojic acid, 3-nitoproprionic
  acid, aflatoxin B-1, aspergillic acid.
• Alternaria tenuazonic acid, alternariol,
  altertoxins.
• Aspergillus niger naphtha-pyrones, malformins.
• Also can make Orchratoxins and Sterigmatoeystin
  toxins.

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Other Molds of Concern and Their Mycotoxins.

• Cladosporium herbarum cladosporic acid.
• There are over 400 more mycotoxins.
• Cryptosporidia transient flu in normal patients.
  Can kill a immunocompromised patient. May respond
  to Diflucan.
• Histoplasmosis Capsulatum. Coccidiomycosis,
  Blastomycosis. Dont forget these.

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Coccidiomycosis spherule with endospores
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Coccidiomycosis Prevalence in the US
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Paracoccidiomycosis with Buds and Giant Cell
Formation.
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Some Known Clinical Responses to Fungi.

• Organic toxic dust syndrome Can come from a
  single exposure. Flu-like, not immune mediated.
• Hypersensitivity pneumonitis- Repeated exposures,
  immune mediated. Can lead to interstitial
  fibrosis in rare cases.
• Fungal sinusitis.
• Activation or aggravation of bronchial asthma or
  other allergic manifestations.

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Common Symptoms Found in Indoor Mold Exposures.

• Generally non-specific.
• Skin itching, rashes, periorbital swelling.
• GI - Anorexia, diarrhea.
• Muscular pains. Flu-like.
• Low grade fever.

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Common Symptoms Found in Indoor Mold Exposures.

• Respiratory symptoms rhinitis, sinusitis,
  asthma, SOB, chest discomfort, epistaxis.
• Neurologic concentration, memory, fatigue,
  headaches, unsteadiness.

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Diagnosis

• Reasonable suspicion on the part of the health
  care provider or the patient.
• Screening or IAQ testing showing presence of
  toxigenic mold.
• Rule out confounding variables.
• Consider toxigenic and allergic testing to
  confirm correlation.

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Testing

• Blood mycotoxins. PCR, IgE, IgA and IgG fungal
  tests. Precipitins.
• Blood allergy or skin allergy testing.
• General tests to rule out other causes of these
  symptoms. HIV, ANA.
• Pulmonary function testing.
• Imaging studies of sinuses, chest etc. as
  appropriate. Immune studies.
• May test for autoantibodies to glial and neuronal
  tissue.

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Treatment for Indoor Mold Related Symptoms

• Remove source of water or humidity. Keep it below
  55.
• Remove the subject from the environment. In most
  cases it is reversible.
• Remediate using professional assistance.

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Treatment (Ctd)

• Recheck IAQ afterwards.
• Palliative therapy, antihistamines, dietary,
  nutritional, emotional, immunotherapy.
• Trial of itraconazole or fluconazole?
• Trial of mold yeast free diet?
• Natural anti fungals - caprylic acid, Pau d
  Arco?

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Experimental Therapies.

• Xolair and Anti IgE RhumAb.
• Valinomycin is produced by a bacterium
  (Streptomyces griseus) living closely associated
  with the fungus Stachybotrys is a poison in sick
  buildings that is being investigated.
• Anidulafungin (Versicor).
• Voriconazole (Pfizer).

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Natural or Alternative Approaches That Have
Reportedly Helped Animal Models

• Quinolones found in Taheebo bark (Pau DArco).
  Other herbs curanderos.
• Dietary modification and improving nutritional
  status with vitamins.
• Immunostimulants Astragalus, etc.
• Cognitive therapy.
• Homeopathy?.

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Preventing Mold Buildup.

• Use air conditioner or dehumidifier during humid
  months.
• Be sure home has adequate ventilation, including
  exhaust fans in kitchen and bathroom.
• Use mold inhibitors in paints.

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Preventing Mold Buildup.

• Clean bathroom with mold killing products.
• Do not carpet bathroom.
• Remove and replace flooded carpets.
• Clean small areas with bleach while wearing
  protective mask.
• Seek services of a certified industrial hygienist
  if larger areas are involved.

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Recent Conference on Mycotoxins

• Bioaerosols, Fungi and Mycotoxins Health
  Effects, Assessment, Prevention and Control.
  Edited by Eckhardt Johanning MD 2001, Mount Sinai
  School of Medicine, Department of Community
  Medicine, Fungal Research Group.
• This publication is from the Third International
  Conference on Fungi, Mycotoxins and Bioaerosols
  held Sept 23-25 1998.

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Summary

• Most cases of mold related illness get better
  once the problem is remediated.
• For those remaining, it is useful to determine
  extent of problems objectively and treat in a
  holistic manner (mind and body). It is important
  to separate those who are allergic, those who are
  probably toxic and those who are frightened or
  have any combination of these three.
• Education is very important.