MYCOLOGICAL INSTITUE

for the study of

FUNGAL MOLD IN HUMAN HABITATIONS

2000               Research Association in EU US UK          2006

ISHAM is a world wide organisation that represents all scientists and doctors with a special interest in fungal diseases. ISHAM is an independant society that is non-political and non-discriminatory. It exists solely to encourage and facilitate the study and practice of all aspects of medical and veterinary mycology.

MYCOLOGY   RESEARCH

Link to the International  site at   njmycological.ath.cx  FMHH

The Mycological Society of America is a scientific society dedicated to advancing the science of mycology - the study of fungi of all kinds including molds,yeasts, lichens, plant pathogens, and medically important fungi.  

ABOUT MYCOLOGY, FUNGI and HUMANS

 
SELECT PRO BONO CASES ACCEPTED FOR CLINICAL RESEACH PURPOSES. CONTACT:
mycological intitute mold in human habitations 
Physicians Short Course in Clinical Mycology and Fungal Infections
1. Introduction to the Microbiology of Clinically Relevant Fungi
2. Spectrum of Human Mycoses
3. Disease Mechanism of Fungi
4. Current Antifungal Agents
5. Diagnostic Protocol for Mold Illness  

**Introduction to Human Aspergillosis - Diagnosis and Treatment  

In general, immuocompetent humans have a high level of innate immunity to fungi and most of the infections they cause are mild and self-limiting. This resistance is due to:

Fatty acid content of the skin
pH of the skin, mucosal surfaces and body fluids
Epithelial turnover
Normal flora
Transferrin
Cilia of respiratory tract

 

           

Aspergillus 

(epistemology, pathology, clinical presentations and therapies)

When fungi do pass the resistance barriers of the human body and establish infections, the infections are classified according to the tissue levels initially colonized . This is often experienced in the hospital setting although underreported in the USA.  Recent studies in France indicate nearly half of the nosocomial infections (hospital acquired infections) of Aspergillosis result in death even when the surgery is successful   by this fungal mold.

More commonly the clinician will encounter fungal mold infections as a topical presentation such as in the case of the common dermatophytes typically in the scalp and nails.

clinical presentaion of dermatophytes

Classes  of Mold Infection (Dermatophytes) at Tissue Level

A. Superficial mycoses - infections limited to the outermost layers of the skin and hair. The superficial mycoses are:
 

Disease Etiological Agent  Symptoms  Identification of organism

Pityriasis versicolor 

Malassezia furfur     

hypopigmented macules 

"spaghetti and meatballs" appearance of organism in skin scrapings

 

Tinea nigra 

Exophiala werneckii 

black macules

black, 2-celled oval yeast in skin scrapings 

Black piedra 

Piedraia hortai

black nodule on hair shaft 

black nodule on hair shaft composed of spore sacs and spores 

White piedra 

Trichosporum beigelii 

creme-colored nodules on hair shaft 

white nodule on hair shaft composed of mycelia that fragment into arthrospores

B. Cutaneous mycoses - infections that extend deeper into the epidermis, as well as invasive hair and nail diseases.

These diseases are restricted to the keratinized layers of the skin, hair and nails. Unlike the superficial mycoses, various cellular immune responses may be evoked, causing pathologic changes in the host that may be expressed in the deeper layers of the skin. The agents causing these diseases are termed dermatophytes. The diseases are referred to as ringworm or tinea. All of the dermatophytic diseases are caused by members of three genera, Microsporum, Trichophyton and Epidermophyton, which comprise 41 species. The cutaneous mycoses are:
 

Disease  Etiological Agent  Symptoms Identification of organism
Tinea capitis  Microsporum sp. Trichophyton sp. Epidermophyton sp.  ringworm lesion of scalp

presence/absence and shape of micro- and macroconidia in scrapings from lesion 
Tinea corporis  Microsporum sp. Trichophyton sp. Epidermophyton sp ringworm lesion of trunk, arms, legs  presence/absence and shape of micro- and macroconidia in scrapings from lesion 
Tinea manus Microsporum sp. Trichophyton sp. Epidermophyton sp ringworm lesion of hand presence/absence and shape of micro- and macroconidia in scrapings from lesion 
Tinea cruris "jock itch" Microsporum sp. Trichophyton sp. Epidermophyton sp ringworm lesion of groin presence/absence and shape of micro- and macroconidia in scrapings from lesion 
Tinea pedis"athlete's foot" Microsporum sp. Trichophyton sp. Epidermophyton sp ringworm lesion of foot presence/absence and shape of micro- and macroconidia in scrapings from lesion 
Tinea unguium Microsporum sp. Trichophyton sp. Epidermophyton sp infection of nails presence/absence and shape of micro- and macroconidia in scrapings from lesion
Ectothrix Microsporum sp. Trichophyton sp. Epidermophyton sp infection of hair shaft surface  mycelium and spores on hair shaft 
Endothrix Microsporum sp. Trichophyton sp. Epidermophyton sp infection of hair shaft interior mycelium and spores in hair shaft

C. Subcutaneous mycoses - infections involving the dermis, subcutaneous tissues, muscle and fascia

        These infections initially involve the deeper layers of the dermis, subcutaneous tissue or bone. Most infections have a chronic  or insidious growth pattern, eventually extending into the epidermis and are expressed clinically as lesions on the skin    surface. They are initiated by trauma to the skin and are difficult to treat and surgical intervention (excision or amputation)  is frequently employed. The subcutaneous mycoses are:
 

Disease 
Etiological Agent
Symptoms
Identification of Organism
Sporotrichosis  Sporothrix schenckii  Nodules and ulcers along lymphatics at site of inoculation Budding yeast in tissue exudate that converts to mold with "rosette pattern" of conidiation on culture at 25oC. 

Chromoblastomycosis

 

 

 

 

Fonsecaea pedrosoi 

Fonsecaea compacta 

Wangiella dermatitidis 

Warty nodules that progress to "cauliflower-like" appearance at site of inoculation 

 

 

 

Copper-colored spherical yeast called "Medlar Bodies" in tissue 

 

 

Mycetoma 

 

 

 

Pseudallescheria boydii 

Madurella grisea 

Madurella mycetomatis

Draining sinus tracts at site of inoculation

 

 

White, brown, yellow or black granules in exudate that are fungal colonies

 

 

D. Systemic Mycoses - Infections that originate primarily in the lung (RECENT CASE: Aspergillus niger Fungal ball- Kendall Park, NJ 2004) and may spread to many organ systems, eye, intestines, spine, heart (endocarditis, pericarditis ) brain, kidney etc.

Aspergillosis of lungs

Aspergillus in the Lung

We investigated a habitation in 2006 in Monmouth County, New Jersey. A 65 year male initially diagnosed with a brain cancer, then as Aspergillosis. . Lab culture analysis revealed Cladophialophora (Xylohypha) bantiana. This pathogen was found extensively in the damp basement.

Brain abcess due to Claophilaphora bantiana

Unlike most other fungi, the five systemic mycotic agents are inherently virulent. Each species has biochemical and structural   features that enable it to evade host defenses. The primary focus of infection is the lung but secondary infection may occur  elsewhere in the body. The five etiological agents are identified by their morphology on agar plates (saprobic phase) and in  tissue (parasitic phase):        Dimorphic with mold to yeast transition when infecting susceptible species. Yeast cells are relatively small. Saprobic phase   shows tuberculate macroconidia.

Histoplasma capsulatum
Saprobic Phase            Parasitic Phase

        Dimorphic with mold to yeast transition when infecting susceptible species. Yeast cells are medium size with thick walls.

Blastomyces dermatitidis
Saprobic Phase            Parasitic Phase

        Dimorphic with mold to yeast transition when infecting susceptible species. Yeast cells have multiple buds.

Paracoccidioides brasiliensis
Saprobic Phase            Parasitic Phase

        Dimorphic with mold to spherule transition when infecting susceptible species. Spherules are multinucleate.

Coccidioides immitis
Saprobic Phase            Parasitic Phase

        Monomorphic with yeast phase only. This is the only pathogenic yeast with a capsule. The capsule is extremely large.

Cryptococcus neoformans
Saprobic Phase            Parasitic Phase

E. Opportunistic mycoses  - infections in patients with immune deficiencies who would otherwise not be infected

        Opportunistic mycoses are seen in those people with impaired host defenses such as occurs in
 

  •  AIDS
  • Alteration of normal flora
  • Diabetes mellitus
  • Immunosuppressive therapy
  • Malignancy 

     The major opportunistic mycoses include:
     

    Disease  Etiological Agent Symptoms Identification of organism
    Candidiases Candida albicans Creamy growth on various areas of body Budding yeast, septate hyphae, pseudohyphae in tissue. Germ tubeformation in serum
    Aspergillosis  Aspergillus fumigatus  "Fungus ball" in tissue  Morphology of asexual fruiting structure 
    Zygomycosis Rhizopus sp. Absidia sp. Mucor sp.  Various Morphology of asexual fruiting structure and mycelium

    Aspergillus

            

    Rhizopus

    Asexual fruiting structure of Aspergillus species, illustrating septate hyphae, conidiophore, vesicle, phialides and conidiospores                     Asexual fruiting structure of Rhizopus species, illustrating sporangium, sporangiophore, sporangiospores, coenocytic hyphae and rhizoids.
     
    F. Bronchial Asthma - Fungal mold appears to be a leading cause of asthma and certainly plays a role in aggravating asthmatic conditions as  demonstrated in recent studies where IgE is clearly elevated when contact is made with mold in a 2004 study.  
     

    F. Sarcoidosis (or sarcoid) is an immune system disorder characterized by non-necrotising granulomas (small inflammatory nodules). Virtually any organ can be affected, however, granulomas most often appear in the lungs (D860) or the lymph nodes (D861). Symptoms can occasionally appear suddenly but more often than not appear gradually. When viewing X-rays of the lungs, sarcoidosis can have the appearance of tuberculosis or lymphoma.


    Antifungal Agents

    Amphotericin B - Polyene Antibiotics (macrolides)

    Amphotericin B - binds to ergosterol moiety in the plasma membrane causing derangement of the membrane integrity and leakage of cytoplasmic contents. Administered systemically.

    Amphotericin B

    Nystatin - binds to ergosterol and disrupts plasma membrane. Highly insoluble and toxic and therefore used topically only.

    Azoles

    Block ergosterol synthesis at one or more sites with the accumulation of 14 -methyl sterol (which replaces ergosterol in the plasma membrane causing selective leakage and increased osmotic sensitivity). They also disrupt chitin synthesis. All effects are due to the binding to cytochrome P-450.
     

  • Butoconazole (Suppository, Topical)
  • Clotrimazole (Topical)
  • Econazole (Topical)
  • Fluconazole (Oral, Topical)*
  • Itraconazole (Oral)
  • Ketoconazole (Oral, Topical)*
  • Miconazole (IV, Intrathecal, Topical)
  • Oxiconazole (Topical)
  • Sulconazole (Topical)
  • Terconazole (Suppository, Topical)


    Allylamines

    Naftifine - Binds to and inhibits squalene epoxidase which blocks ergosterol synthesis . Terbinafine - Binds to and inhibits squalene epoxidase which blocks ergosterol synthesis .

    Naftifine

                                  

    Terbinafine

     

     

    Echinocandins

    Echinocandins are a new option for fungal infections. They are fungicidal and less toxic to the host by virtue of their novel mechanism of action. They are b-1, 3-glucan synthase inhibitors. FDA, USA has approved caspofungin for treatment of invasive aspergillosis in patients who fail to respond or are unable to tolerate other antifungals. Two other agents are in phase III clinical trials – micafungin and anidulafungin. Caspofungin among echinocandins has been studied vastly and offers apparent exciting advantages of a broad spectrum of activity including strains of fungi resistant to other antifungal agents, tolerability profile, with no nephrotoxicity and hepatotoxicity as compared to azole and macrolide antifungals. It may be effective in AIDS-related candidal esophagitis, oropharyngeal candidiasis, fungal pneumonia and nonmeningeal coccidioidomycosis. Clinical trials are required to ascertain their safety in special groups—pediatric, pregnant and nursing mothers. Echinocandins provide an exciting option for combination therapy with other antifungals in fulminant fungal infections.

     

       
     

     

    Pyrimidine analogs

    Flucytosine - It is deaminated to fluracil where it is either (1) incorporated into RNA in place of uracil where it inhibits protein synthesis or (2) metabolized to 5-fluorodeoxy-uridylic acid where it inhibits thymidylate synthetase, thus blocking DNA synthesis.
    Pyrimidine 
      
  analogs

    Miscellaneous types

    Griseofluvin

    Haloprogin

    Griseofulvin - causes disruption of the mitotic spindle by interacting with polymerized microtubules through binding to microtubule protein. Administered systemically for dermatophytic infections.                         Haloprogin - a halogenated phenolic ether administered topically for dermatophytic infections.
    Ciclopirox 
            
  olamine Tolnaftate
    Ciclopirox olamine - a topical for the treatment of dermatophytic infections and Candida albicans. Tolnaftate - a thiocarbonate used to treat dermatophytic infections.

    Potassium iodide (KI) - Given orally for sporotrichosis 

    5. Diagnosis of mold illness and fungal diseases

    We refer you to Dr. Ritche Shoemaker's Diagnostic Protocol for Mold Related Illness  


    Summary

    1.    Morphologically fungi are unicellular (yeasts) or multicellular (hyphae). Some fungi can alternate between the two forms
            (dimorphic fungi).2.    Hyphae are branching, threadlike, tubular filaments that either lack cross walls (coenocytic) or have cross walls (septate).

    3.    Hyphae reproduce asexually via the formation of spores termed microconidia or macroconidia.

    4.    Fungi produce toxins such as ergot alkaloids, psychotropic agents and aflatoxins.

    5.    Visualization of fungi in human tissue is accomplished by treatment with 10% KOH and staining with lactophenol cotton blue,
            Grocott silver stain, hematoxylin or eosin.

    6.    India ink may be used as a negative stain to emphasize the capsule of yeast.

    7.    The physician can use an ultraviolet lamp (Wood's lamp) to detect fluorescent compounds produced by fungi growing in or on
            human tissue.

    8.    Fungal diseases are classified according to their depth of penetration of human tissue. Thus, there are the superficial mycoses,
            cutaneous mycoses, subcutaneous mycoses and systemic mycoses.

    9.    The superficial mycoses include pityriasis versicolor, tinea nigra, black piedra and white piedra.

    10.    The cutaneous mycoses (tineas or ringworms) are restricted to growth in the keratinized layers of the skin, hair and nails.

    11.    The subcutaneous mycoses penetrate the dermis, subcutaneous tissue, muscle and fascia. These include sporotrichosis,
            chromoblastomycosis and mycetoma.

    12.    Systemic mycoses originate in the lung and then may spread to many organ systems. These include histoplasmosis, North
             American blastomycosis, South American blastomycosis, coccidioidomycosis and fungal meningitis.

    13.    Fungi are most commonly cultured on Sabouraud's agar or Mycosel agar.

    14.    Opportunistic mycoses are often secondary to other diseases that compromise host immunity such as AIDS, diabetes, and
            malignancy.

    15.    Antifungal agents are classified according to their chemical structure as macrolides, azoles, allylamines, pyrimidine analogs
            and miscellaneous.

    16.    The polyene antifungals are amphotericin B and nystatin which bind to ergosterol in the plasma membrane, thus disrupting it.

    17.    The azole antifungals include fluconazole and ketoconazole plus numerous others. They all block ergosterol synthesis by
            binding to cytochrome P-450.

    18.    The allylamines include naftifine and terbinafine which inhibit squalene epoxidase, thus blocking ergosterol synthesis.

    19.    The pyrimidine analogs such as flucytosine incorporate into RNA and/or DNA thus blocking protein synthesis or DNA
            synthesis.

    20.    The miscellaneous antifungals include griseofulvin, haloprogin, ciclopirox olamine, tolnaftate and potassium iodide.

    21.    The three genera of dermatophytes are Microsporum, Trichophyton and Epidermophyton.

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