By Jack Dwayne Thrasher, Ph.D.

(505) 937-1150 - Cell

Email: toxicologist@drthrasher.org

Molds and Human Diseases

INTRODUCTION

I took my first course in microbiology, followed by medical mycology while an undergraduate student at Long Beach State College, Long Beach, California. At that time it was recognized that molds mainly caused plant diseases. On the other hand approximately 100 of some 1.5 million mold species caused human disease. A few more species have been added, resulting from identification of infections in immunocompromised individuals. Presently, the general public is concerned about llnesses caused by molds because of contamination of indoor environments (domestic, office buildings, hospitals, etc.) by these organisms. This communication briefly reviews human diseases caused by molds. Infections, mycotoxins and illness caused by individual indoor molds will be covered in more detail in separate communications. If you wish to obtain more detailed information on diseases caused by molds, such data can be gleaned from textbooks on medical mycology and the scientific/medical literature on the subject.

For convenience, human mycotic infections (mycosis) are grouped into superficial, subcutaneous and systemic (deep) mycoses. Superficial mycoses (skin hair, nails), maybe chronic, resistant to treatment, seldom debilitating and can be transferred from human to human or from pets to humans. The deeper lying mycoses (subcutaneous and systemic) are usually acquired infections. The mold spores enter the body through injured skin invading subcutaneous tissues, spreading systemically through lymphatic vessels. Infection from fungi occurs from inhalation, penetration of the skin and ingestion.

It is thought that pathogenic fungi in infecting tissues produce no mycotoxins. However, they regularly induce hypersensitivity to their metabolites and cellular constituents. In addition, they can cause chronic granulomas ranging from necrosis to abscesses. Finally, they can invade other tissues via lymphatic channels.

THE MYCOSES

(1) Superficial (skin) Mycoses: These fungi invade only superficial keratinized tissue (skin, hair, and nails), but not invade underlying deeper tissues. Some of these fungi include: Trichophyton sp. (arthroderma, mentagrophytes, ruburm Microsporium nannizzia & canis, Epidermophyton floccussum, Tinea sp. (pedis, corporis, cruris, capitis, barbae, unguium, versicolor, and horrtae. The most common skin lesions are by the Tinea spp: Athlete’s foot, and ring worm, jock itch and nail beds. The lesions are usually red, scaly and itchy. Other superficial mycoses not listed in the Table below are Tinea versicolor (lesions on skin of chest, back, abdomen, neck & upper arms. Lesions are de-pigmented to brownish red); Tinea nigra (light brown to blackish macular areas on palmar or plantar skin); Piedraia hortae (hard black nodules of scalp hair and Trichosporon cutaneum (white to light brown nodules on axillary, pubic, beard and scalp hair.

This Table was adapted from Jawetz et al, 1989.

Skin Diseases	Location of Lesions	Clinical Appeareance	Most Responsible Fungii
Tinea corporis (ringworm)	nonhair smooth skin	circular patches, red, vesiculated border, central scaling, itchy	M. canis, T. mentagrophytes
Tinea paedis (Athelete's foot)	Between toes	Itching, red, vesicular, scaling, fissures	T. rubrum, mentagrophyte & E. floccosum
Tinea cruris (Jock itch)	Groin	Erythematous scaling lesions, itchy	T. rubrum, mentagrophyte & E. floccosum
Tinea capitis	Scalp hair; endothrix(follicle Ecothrix(shaft)	Circular blad paatches, short hair stubs, bronek shafts; fluoresce	M. canis, T. tonsurans
Tinea barbae	Beard hair	Edematous, erythematous lesions	T. rubrum, T mentagrophytes, & E. floccosum
Tinea ungulum	Nails	Nails thickened, crumbly, discolored, lusterless	T. rubrum, T mentaagrophytes, & E. floccosum
Dermatophytid	Sides & flexor aspects of fingers, palm, any site on body	Vesicular to bullous lesions, itchy	No fungi in lesions, may have secondary bacterial infection

(2) Subcutaneous Mycoses: These fungii invade the deeper (subcutaneous) layers of skin. It is believed that they have to be introduced into the subcutaneous tissues. Once established, they are slow growing and can spread to other organs via lymphatic drainage. The most common mycoses are:

(2a) Sporotrichosis: (Sporothrix schenckii) This fungus lives on plants or wood. The lesions are granulomatous, spreading along lymphatic channels. The organism is traumatically introduce into the skin. The disease is most common in nursery workers, miners and gardeners appearing as subcutaneous nodules.

(2b) Chromomycosis: This is a slowly progressive granulomatous infection of the skin caused by several species of black molds (Phialophora verrucosa, Phialophora (Foncsecaea pedrosoi, and Cladosporium carrionii.) The organisms gain entrance by trauma to skin of the legs or feet, leading to cauliflower-like nodules with crusting and abscesses. Pigmentation is from olive-green to brown or black. Chromomycosis occurs mainly in the tropics. Protective clothing, shoes and leggings are the best prevention.

(2c) Mycetoma: Mycetoma are localized, swollen lesion with granules of compact colonies draining from sinus tracts. They are caused by a variety of fungii and actinomycetes (the filamentous bacteria see below). Mycetoma develop when these soil organisms are implanted by trauma into the subcutaneous tissue of the skin. The disease occurs worldwide in people who do not wear shoes. White, yellow, red or black granules are extruded in pus. Causative organisms identified from lesions include species of Madurella, Phialophora, Acrenomium, Norcardia brasiliensis and Actinomadura madurae.

(3) Systemic Mycoses: These infections are caused by soil fungi via inhalation and are initially asymptomatic. In the asymptomatic phase of the disease, dissemination to other organs can occur, which is often fatal. The infections usually occur in susceptible individuals as a result of genetics or a compromised immune system (cancer chemotherapy, organ transplant, etc.).

(3a) Valley Fever (Coccidiodes immitis): A soil fungus that is endemic to arid regions of the United States (San Joaquin and Sacramento valleys of California, Tucson and Phoenix Arizona, Western Texas). It is also found in Central and South America.

Infection occurs via inhalation of arthrospores, particularly following a dry spell with dust storms. The spores can be carried some distance, with infection being reported in residents of San Francisco (C. immitis free area), California in 1977 following a drought and dust storms in the western USA.

Following inhalation of arthrospores, a respiratory infection occurs, which is usually self-limiting. The lung infection is most often asymptomatic and is diagnosed by IgM and IgG precipitating antibodies to the fungus 1-2 weeks after onset. Some individuals develop an influenza-like illness with fever, cough, malaise and aches. About 5-10 % of infected people develop hypersensitivity reactions, characterized by erythema nodosum or erthema multiforme. Thus, the symptom complex has been called “valley fever” or “desert rheumatism”.

The disease can disseminate and is fatal in less than 1 % of the infected individuals. Blacks, Filipinos, Mexicans, pregnant women and immune compromised individuals are most susceptible. Coccidioidomycosis lesions occur in many organs, bones, and central nervous system with histological appearing granulomas and wide spread suppuration. Remissions and exacerbations often occur during the course of the infection. Treatment is chemotherapy that may or may not be beneficial. Coccidioidomycosis is a serious infection in immunocompromised patients.

(3b) Histoplasmosis (Histoplasma capsulatum): This is soil fungus found throughout the world. Infection occurs by inhalation of conidia (spore structures). The organism causes an intracellular mycosis of the reticulo-endothelial system R.E. system). Infected persons develop a positive skin reaction to tests with an antigen (Histoplasmin).

Histoplasmosis occurs in many parts of world. In the USA it is found in the central eastern part of the country. The organism grows in soils mixed with fecal matter from birds (hen houses) and bats (bat guano). Individuals in these environments can obtain a massive infection.

Inhaled conidia are taken up by macrophages and develop within these cells. The organism is then disseminated throughout the body through the R.E. system. Small granulomatous or inflammatory foci in the lungs and spleen become encapsulated and calcified. In heavy exposures pneumonia may develop. Chronic cavitary histoplamosis can develop in adult males. Disseminated infections can occur in children, the elderly and immuno-suppressed individuals.

The R.E. system is usually involved with lymphoadenopathy, enlarged spleen, and liver, high fever, anemia and a high mortality. Focal areas of necrosis with granulomas can be found in many organs (liver, spleen, bone marrow).

Diagnosis is by sputum specimens, microscopic examination, culture, serology and skin test. Individuals with symptomatic primary pulmonary histoplasmosis usually recover with supportive therapy and rest. Dissimenated infections are treated with systemic chemotherapy.

(3c) Blastomycosis (Blastomyces dermatitidis): This is a chronic granulomatous disease that occurs in North and South America and Africa. Infection is believe to occur from inhalation. Mild and self-limiting cases are usually not recognized. Disseminated infections involve the skin leading to ulcerated verrucous granulomas with an advancing border and central scaring. Microabscesses are not uncommon. Lesions of the prostate, bone, epididymis and testis have been reported. Blastomycosis is a common finding in dogs in endemic areas and is believe not to be transferred to humans from animals. Diagnosis is by specimens, microscopic examination, culture, animal inoculation and serology. The most beneficial treatment is ketoconazole, 400 mg/day.

(3d) Paracoccidioidmycosis (Paracoccidioides brasiliensis): This is the predominant systemic mycosis of rural Latin America, mainly infecting farmers. Infection occurs by inhalation with early lesions in the lungs. Dissemination then occurs to the spleen, liver, mucous membranes (particularly oral cavity), and skin. Granulomas and microabcesses occur in involved tissues. Diagnosis is by sputum, microscopic examination, culture, skin tests and serology. Sulfonamides and ketoconazole have been effective in management of the infection.

4) Opportunistic Mycoses: These are fungi that do not normally cause humans disease. However, they may do so in individuals with altered host defense mechanisms. These infections may involve any or all organs in the immuno-compromised individual.

(4a) Candidiasis (Candida albicans and other C. species): Candida species, particularly, C. albicans, are known to cause mild superficial infections through dissemination and sepsis. Thus, infants can develop an oral infection, Thrush, which is enhanced by antibiotics, corticosteroids, high levels of glucose and a compromised immune system. Vulvovaginitis can occur in females; diabetes, pregnancy, progesterone, and antibiotic therapy predisposes a woman to the infection. Other superficial sites for infection include skin and nails.

Candida may be a secondary invader of the lungs, liver, kidneys and other organs where pre-exisiting disease is present (cancer, tuberculosis, in immuno-compromised individuals, as well as following surgery. C. parapsilosis causes infections in addicts and may be associated with implanted prosthetic heart valves.

The most preventative measure for Candidiasis is prevention of disruption of normal balance of microbial flora, i.e. avoidance of broad spectrum antibiotics, cortico-steriods and other anti-microbial agents.

(4b) Cryptococcosis (Cryptococcus neoformans): This Is a yeast that infects humans via the respiratory tract. The infection may be either asymptomatic or symptomatic. Massive inhalation may result in progressive systemic disease involving major organs, including the brain. Usually, it is an opportunistic organism with infections occurring in immuno-compromised individuals, beginning with pulmonary involvement that disseminates to the central nervous system. The infection process is most often subliminal, eventually leading to a meningitis. Cryptococcal meningitis can fluctuate over time, but all untreated cases are usually fatal. Bird droppings are the major source of C. neoformans, with pigeon excreta being an excellent growth medium.

(4c) Aspergilliosis (Aspergillus fumigatus and other A. species): Aspergilliosis is a group of mycoses with diverse causes and pathogenesis caused by A. fumigatus and other species.

Pulmonary aspergilliosis may occur in distinct forms (1) a “fungus ball” growing in a pre-existing cavity, e.g. tuberculous cavity, paranasal sinus, bronchiectasis. This condition is usually non-invasive; (2) An active invasive granuloma spreading in the lungs causing necrotizing pneumonia, hemoptosis and secondary involvement of other organs. This occurs mainly in immune compromised individuals; and (3) allergic pulmonary aspergilliosis with asthma, eosinophilia, and high serum serum IgE. Diagnosis is dependent upon demonstration of the organism in tissue biopsies.

(4d) Zygomycosis: The extensive literature on the Zygomycoses has been reviewed by Ribes et al, 2000. Zygomycoses are fungal infections caused fungi within this phylum Zygomycota; the two families containing human pathogens are Mucorales and Entopmophthorales. Usually, these organisms invade tissues of individuals suffering from diabetes mellitus, extensive burns, leukemia, lymphoma, other chronic illnesses or immunosuppression. However, infections and/or hypersensitivity reactions can occur in normal healthy people. The various organisms responsible for human infections will be summarized below.

(4d1) Rhizopus spp: Several species of the genus Rhizopus cause human disease. The spores are transmitted by respiratory, percutaneous and gastrointestinal routes. Most infections involve rhinocerebral or pulmonary sites. Respiratory infections have been associated with contaminated air conditioning filters and construction dust in a hospital environment, as well with inhalation of garden compost. Skin infections has occurred from spore contaminated dressings over surgical wounds. Oral transmission via contaminated tongue depressors, old bread, fermented milk and cereal is believed to cause gastrointestinal infections. Rhizopus spp. are predominanatly opportunistic causing infections in diabetics and immune compromised individuals (e.g. leukemia, lymphoma, immunosuppressive regimens). Allergic pulmonary disease does occur in immune competent individuals. For example, inhalation of spores in saw mills (wood cutter’s disease) and malt industries leads to a hypersensitivity response rather than invasive infection.

(4d2) Mucor spp: Several species of the genus Mucor cause infections in humans. In general, these are of two types: (1) Immune competent individuals predominantly have skin and nail infections; (2) Immunocompromised patients tend to have invasive solid-organ infection, e.g. leukemia, aplastic anemia, organ and bone marrow transplantation, kidney disease, diabetus mellitus, asthma, iron overload, burns, and prednisone therapy. Rhinocerebral and pulmonary disease occur by inhalation of spores. Intestinal tract infections probably occur from the ingestion of contaminate food and herbal preparations. Skin infections result from percutaneous exposures.

(4d3) Other Zygomycoses: Several other Zygomycetes have been reported to cause human infections. In general, the number of patients involved are small and are immunocompromised. Only the organisms will be listed. If you desire additional information see Ribes, et al 2000: Rhizomucor pusillus; Absidia corymbifera; Apophysomyces elegans; Saksenaea vasiformis; Cunninghamella bertholletiae; Cokeromyces recurvatus; Syncephalastrum racemonsum; Mortierella spp; Basidiobolus ranarum; and Conidiobolus spp.

5) Actinomycosis: The Actinomycetes are a heterogeneous group called filamentous bacteria. Most are free-living soil organisms, while anaerobic species (Norcardia, Streptomyes) are normal oral flora. Actinomycosis is a chronic suppurative disease forming draining sinus tracts and spreads direct extension. The infections usually involve the face, neck tongue or mandible. Pulmonary infections occur in about one-fifth of the cases leading to abscesses and emphysema. Pelvic actinomycosis has been reported in women who have intrauterine contraceptive devices. The organisms suspected in human disease are Actinomyces israelii and Arachnia spp.

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