Re: Dr. Marinkovich paper on use of anti-fungals

January 14, 2010

Fungal Hypersensitivity: Pathophysiology, Diagnosis, Therapy

I. Introduction

The comments contained herein are those of a clinical immunologist whose major

professional activity is patient care. Over the last several years as the

general awareness of fungal exposure as a cause of illness has grown, more and

more patients have been presenting themselves for diagnosis and treatment after

exposure to homes and offices heavily contaminated by fungi. The Internet has

come to play a major role in the dissemination of good, and some not so good,

information about fungal diseases and the number of patients has mushroomed.

Most American trained physicians have had little instruction in mycology and

tend to dismiss or minimize the possibility of fungal illness except for certain

generally accepted special situations. These would include immunologically

deficient patients, Candida infections in women, thrush in newborns, skin

infections such as ringworm and athlete's foot, and lung infections in areas

endemic for histoplasmosis or coccidioidomycosis. Even allergists who limit

themselves to skin tests for diagnosing hypersensitivity ignore patients

complaining of serum sickness like symptoms (e.g. headaches, rash, malaise,

joint pain, etc.) following exposure to moldy environments and often refer them

for psychiatric care (Terr, 2001). The unfortunate patient has nowhere to turn

except to those few physicians who have listened to their patients, believe what

they say and accept the challenge to try to help. These physicians have gone to

the Internet or the medical literature and developed scientifically inspired

diagnostic and treatment programs that have proven to be helpful to their

patients. I stand among these physicians and I would vigorously defend the

scientific basis and efficacy of my approach to the diagnosis and treatment of

patients suffering from exposure to high ambient levels of fungi in indoor

environments. My best thoughts on the subject are offered herein.

II. Health Effects of Fungi

There is much about the health effects of fungi that is not understood.

Exposure to high ambient fungal spore levels in a water damaged home or building

is, more likely than not, a mixed bag. Not only are more than one fungal genus

likely to be present but bacteria such as Legionella or Actinomycetes may be

present in sufficient quantities to add complexity to the resulting symptoms

(Fink, 1984). Endotoxins are frequently found in abundance when Gram negative

bacteria abound as when sewage is the source of the water (Rylander, 2002). In

addition, insects such as mosquito larvae or other mold-feeding insects (mites)

may be contributing to the airborne organic particle burden. Even large rodent

populations have been discovered in older, run-down, water damaged homes and

buildings. All of these can contribute to the disease patterns seen in patients

exposed to " fungi " in water-damaged structures.

Innate and Adaptive Immunity

Fungal exposure itself can produce a confounding array of symptoms as different

elements of the body's defense systems are triggered. Early in the course of

exposure, the innate immune system can be activated as endotoxins or fungal

elements enter the body tissues. This inflammation can proceed without any

involvement of the adaptive immune system with its antibodies and activated

T-cells (Kauffman, et al, 2000). However, after a few days or weeks of antigen

presentation on an inflamed mucosa, the adaptive system is likely to become

involved as antibodies and T-cells specifically reactive to fungal antigens are

generated. This will add to the inflammation of the affected tissues. And,

finally, fungal elements become directly involved if mycotoxins or other

inflammatory triggers are formed that can cause toxic injury to specific organ

systems. One need only be reminded of such fungal compounds as alcohol,

lysergic acid (LSD), antibiotics, cyclosporin or mushroom toxins to appreciate

the ability of such organic molecules to cause symptoms.

Physicians who treat patients with mold related problems are often challenged by

the variations in the disease symptoms and the multi-organ involvement that are

presumably the result of exposure to environments heavily contaminated with

fungi. They may accept the likelihood that fungal exposure is the cause of

their patient's symptoms, but not understand the underlying pathophysiology.

Still, an attempt is made to treat the patient, essentially by utilizing various

programs that remove the patient from the fungi. Over time, they learn that the

clinical patterns seen in such patients are consistent, the diagnosis can be

accurately made and the response to therapy is very good.

There are other physicians who deny that fungi as encountered in homes or

office-type workspaces are capable of causing illness. These physicians

generally are not primary care givers and can dismiss the patient's complaints

because of their apparent complexity without a consequence. They are better

designated as theorists who base their negativity on arguments that the lack of

sufficient evidence-based proof of a causal relationship of fungal exposure to

human disease proves that such a relationship is not possible. They dismiss all

case reports (Marinkovich et al., 1975) (Fink et al., 1971), epidemiological

studies (Dearborne, 2002) (Etzel et al., 1998) and clinical observations of

experienced clinicians as worthless and such patients as malingerers or

psychiatrically disturbed (Hardin et al., 2003). They seem to lack the vision

to accept the challenge of the possibility that injury to multiple organ systems

may result from exposure to large amounts of fungal derived materials (such as

spores and/or mycotoxins) in a home or office environment. They are wrong and

they can do a great deal of harm. First in denying the patient's symptoms, and

secondly by blocking disability requests from such patients injured by exposure

to fungi in their workplaces. They are guilty of using poor scientific logic

because it is close minded. Such thinking has no place in a medical setting

where there are sick patients who need help.

III. Clinically relevant characteristics of fungi:

Fungi are nature's recyclers. They are extremely abundant in nature, carrying

the mandate to reduce all organic matter to its basic constituents. The

organisms are armed with several features that allow them to satisfy this

mandate. They are microscopic cells which are numerous in all climates where

temperatures are above freezing; they exist in two forms, an active, growing

form and a dormant, hardy, drought resistant and easily wind-borne form (the

spore, also known by the scientific name of conidia). They are superbly

versatile and can grow on virtually any wet surface. They secrete their

digestive enzymes (Kurup, 2003), digest their environment and absorb their

necessary foodstuffs from their immediate, digested environment. Among the

products of digestion are toxins (known as mycotoxins because they are derived

from fungi), which help them control the potential intrusion of competing

organisms into their space. Each of these characteristics plays a role in the

disease patterns seen in fungal illness.

The job of fungal spores is to broadcast the organism widely in the environment.

They are tiny, lightweight and easily airborne. They are in all natural

environments the most prevalent particles in the air at all times. Even at the

height of a pollen season, the pollen particles are outnumbered ten to one by

fungal spores. The human body is marvelously equipped to deal with such large

numbers of potentially infectious particles in the air. The filtering capacity

of the nasal mucosa easily removes the larger spores, greater than 10 microns in

diameter, from the inspired air. Once trapped on the mucosa, the tiny hairs on

mucosal surfaces (cilia) move the particles toward the throat where they are

swallowed and destroyed by the acid in the stomach. Some of the smaller spores,

less than 10 microns in diameter, may be inhaled into the lungs (Geiser et al.,

2000). But even here the normal self-cleansing functions of the lung, which

includes its own cilia and mucus production, are mobilized and particles are

moved upward and swallowed. A small subset of the tiniest spores, less than

three microns in diameter, may be inhaled and trapped in the alveoli and

terminal bronchioles beyond the reach of the cilia. They are handled by the

scavenger cells in the lungs, the alveolar macrophages.

This is extremely important to understanding the pathophysiology of fungal

exposure because once the fungal elements have reached the alveoli they have

entered the tissue space from which they can be absorbed into the blood stream.

IV. Diagnosis

The diagnosis of fungal hypersensitivity syndrome rests on four criteria:

Exposure to an identified heavily contaminated source, appropriate symptoms

temporally related to exposure, high serum specific IgG levels to molds, and

finally a positive response to therapy. IgE antibodies are usually not involved

in hypersensitivity phenomena secondary to exposure to high dose antigen such as

fungi, foods and occupational exposures to organic matter (Fink, 1984). Skin

tests are, therefore of little, if any, value. The fourth criterion for

diagnosis is an essential feature of all medical therapy, namely, the clinical

improvement resulting from a fungal avoidance regimen. When this condition is

not met, the diagnosis must be revisited. Either avoidance is inadequate,

therapy is insufficient or the diagnosis is wrong.

A. Antibodies or lack thereof

Everyone is exposed to fungi in daily living and, therefore, antibodies to fungi

are found in nearly everyone. They have been shown to be protective, except for

patients whose immune systems are inadequate in response. These patients are

extremely susceptible to fungal infection. In such cases, e.g., AIDS patients,

cancer patients (especially if on chemotherapy), transplant recipients on

immunosuppressive drugs, and patients with acquired or congenital immune

deficiency, especially involving cellular immunity, fungal colonization can be

life threatening. In most healthy individuals, the constant exposure to ambient

fungal spore levels is handled easily by normal mucosal cleansing mechanisms and

the ever-vigilant immune system. Ill effects do not generally occur in the

normal population. However, this statement is not true for all otherwise

" healthy " individuals. The extreme example of this is seen in certain

occupational fungal diseases, e.g., farmer's lung (Emanuel et al., 1964), malt

workers pneumonitis (Riddle et al., 1968), etc. where enormous exposures occur

on a daily basis and virtually everyone can be symptomatic. In such cases the

inflammatory changes produced in the lungs can cause severe destruction of lung

tissue, extensive colonization of lungs with fungi and bacteria, and slow

progression to respiratory deficiency and death (Pepys, 1969). Such patients

must be treated aggressively with complete cessation of further exposure, high

doses of systemic and inhaled antifungals (s et al. 2000) (Nark et al.,

2003) and the judicious use of systemic steroids to reduce inflammation and

arrest the progressive damage or remodeling of the lungs (Kaltreider, H.B.,

1993). Steroids actually encourage fungal growth by suppressing the

inflammatory reaction and their use must be carefully monitored to walk the

tightrope between too much steroid encouraging fungal growth and too little

allowing progressive destruction of lung tissue.

B. Individual Variations in Response

The levels of fungi in contaminated homes and office buildings may be quite high

but are generally not nearly as high as encountered in the special occupational

situations previously mentioned above. Still they are high enough to cause

serious illness in non-immuno-compromised individuals (Burr, 2001). A

considerable variation in response to moldy homes among members of the family is

common. In some cases all members of the family are affected with some small

variations in severity and in the organs infected, e.g., skin, lungs, sinuses,

gastrointestinal tract, headaches, etc. In other instances the variation in

severity of illness can be considerable among family members, one person at one

extreme may be quite ill, even disabled, while another at the other extreme has

little to show for the exposure. This is understandable in that not all rooms

in the house may be equally contaminated and those sleeping in the rooms with

highest levels of contamination are likely to have more severe symptoms.

Variations may be seen in the amount of time each individual spends at home.

And then there is genetic polymorphism where each individual is endowed with his

own unique immune responsiveness and two individuals in the same family or

bloodline may respond quite differently to the same exposure. In studies done

with serum sickness where normal, healthy individuals were given different

volumes of horse serum intravenously, some individuals developed symptoms (Von

Pirquet, 1951) with relatively low volumes of serum while others required ten

times more serum to show the same symptoms. The conclusion of these studies was

that everyone was susceptible, but there is a dose dependent susceptibility

among different individuals.

Sustained exposure to airborne fungal spores at levels far below the

occupational disease levels in otherwise normal healthy individuals will produce

symptoms in some percentage of patients. The exact percentage of susceptible

individuals is likely to be low, perhaps under 1% of the population. But with

the widespread contamination of home and workplaces in this country, with

perhaps 30% of the schools, homes and offices involved, the actual number of

affected individuals can easily reach one million. One percent of the

population is about three million individuals and a third of these would be one

million. This is an epidemic. Unfortunately, many of these cases are not

recognized by the medical community and go undiagnosed and untreated. Thanks to

the Internet and the media publicizing the results of litigation involving mold

cases, the public's awareness of the problem has grown. Hopefully, this will

induce more health caregivers to learn about fungal illness.

Hypersensitivity

The human immune response, part of the body's system of adaptive immunity can be

amazingly sensitive. A person allergic to cats can sense the presence of cat

dander in a room months after the cat has departed. And rarely, one reads of a

sudden death from anaphylaxis provoked by exposure to a tiny amount of antigen

such as vespid venom from a single bee sting or the steam rising from a fish

stew, or tiny particles of peanut contaminating a package of almonds processed

on machinery previously used to process peanuts (Samson, 1992). The extreme

sensitivity potential of the immune system is rarely seen but frightening when

it occurs. When the number of individuals exposed to such spore levels is very

high, as seems to be the case today in homes, schools and workplaces, a

significant number of cases will occur. To deny this is akin to denying the

existence of significant pollen or cat allergies because the great majority of

people do not show such symptoms on exposure. Genetic polymorphism is the basis

for a considerable number of differences within the human population and the

immune response, based on the same mechanisms, shows the same wide variations in

response among individuals.

V. Symptoms

While the symptoms seen in patients exposed to high ambient levels of fungal

elements can vary a great deal among different individuals, a fairly consistent

pattern of illness is seen in patients presenting with sufficient symptoms to

warrant seeing a physician. Most patients describe a progression of symptoms

beginning a few months to a few years after the onset of exposure (e.g., moving

into a mold-infested house). Initially the complaints are nasopharyngeal (sore

throats, hoarseness, stuffy nose, transient hearing loss), or pulmonary (cough,

wheezing, shortness of breath). With time, symptoms progress to include

headaches, fatigue, rashes, vertigo, muscle and joint pain, fever, recurrent

sinus or ear infections, etc (Rylander, 1994). Many of these symptoms are the

result of an overactive immune system trying desperately to overcome what it

perceives to be an overwhelming infection. The immune system generates

antibodies to the absorbed materials (or antigens). These antibodies react with

the antigens to form immune complexes, which is all part of the body's normal

immune elimination function. These complexes are quickly taken up by scavenger

cells, which remove the complexes from the circulation thus limiting their

inflammatory effects. When complex formation continues over a long period of

time, this clearing mechanism can become overloaded. The complexes then remain

in the blood stream causing myriad symptoms, known to clinical immunologists as

serum sickness or immune complex disease (Cochrane et al., 1973). To the

patient, the symptoms appear to be a severe, unrelenting flu syndrome. When one

looks up in the older literature the classical symptoms seen in serum sickness,

they are exactly those symptoms the patients with fungal illness describe to

their physician (Von Pirquet, 1951).

Since hypersensitivity states develop only after relatively long exposure times,

normal children under ten years of age do not have significant antibody titers

to fungi. However, when children experience very high exposure levels in the

home or school, measurable antibody levels appear rather quickly, i.e., within a

few months of exposure. Normal mature adults living in temperate or tropical

climates commonly show antibody activity toward fungi and experience symptoms

following unusual exposures. The onset of symptoms often follow exposures by

one or two days, are not recognized for what they are, and are likely to be

diagnosed as a virus infection.

VI. Mycotoxins

Mycotoxins are the most respected of fungal products for their potential to

cause serious illness through their direct biochemical action on key body

functions (Johanning et al., 1996) (Croft et al., 1986) (Leino et al., 2003).

The immune system is not involved. One of these, aflatoxin, is known to be

among the most potent of carcinogens. Another group, trichothecenes, are toxins

released by the fungus Stachybotris atra (also known as Chartarum) as well as

others. There is controversy regarding the role of trichothecene mycotoxins in

pulmonary hemosideroisis (Dearborn et al., 1999). Other toxins can affect

various hormonal, neurological and other body functions to produce serious

health effects (Sorensen, 1999). They are so effective in certain biological

activities that they have been harnessed by the pharmaceutical and food

industries for commercial use such as antibiotics, immune suppressants to

control graft rejection, medicine for cholesterol control, and enzymes used in

food processing and preservation. Mycotoxins are produced by fungi under

specific growth conditions and their role in human illness is not well

understood. Exposure to certain mycotoxins producing organisms such as

Stachybotrys seem to cause neurological damage seen as short-term memory loss,

cognitive dysfunction, inability to concentrate and " fuzzy thinking " . There are

common complaints of patients with fungal illness. The changes seem to be

reversible, at least in part, but they can take years to resolve. Hyperactive

immune systems responding to the influx of fungal antigens following chronic

exposures are much more likely to be a cause of symptoms in most individuals.

VII. The role of IgE and non-IgE

Allergists have accepted the role that fungal spores can play in eliciting

allergy symptoms in susceptible individuals. This is akin to the effects of

other airborne organic particles such as pollen, animal dander and insect dust

The illness affects only individuals programmed genetically to make large

quantities of specific IgE antibodies on exposure to relatively small amounts of

allergen. This is type I immunopathology as defined by Gell and Coomb (Gell et

al., 1964) and involves the release of pre-formed histamine and other

biologically active cytokines from sensitized mast cells and basophils.

Symptoms include watery nasal discharge, sneezing paroxysms, itching of the

naso-oro-pharyngeal mucosa and tearing eyes, and can be significantly disabling.

Symptoms disappear quickly upon cessation of exposure, leaving little, or no,

residual effects. It has been suggested that perhaps five percent of the

population may be affected in this way by fungi, although those numbers will

vary in different climates (e.g., more in Florida than New Mexico). The great

majority of patients presenting with symptoms of fungal illness do not show IgE

antibody to the fungus (Fink, 1984). This may be the result of isotype

switching from IgE to IgG production as stimulation of the immune system

increases. When this happens far more elaborate and damaging immune responses

can be generated by the body following exposure to large amount of fungal

particles, especially when the exposure is chronic. These illnesses were

originally described in association with various occupational exposures in

unprotected workers such as farmer's lung, bagassosis in sugar cane workers, and

many others. More recently such conditions have been identified and studied in

office workers whose workplace is contaminated by fungi, especially in buildings

with closed ventilation systems (Fink, 1984), in individuals exposed to swamp

coolers (Marinkovich et al., 1975) or contaminated air conditioners in the home

(Bavaszak et al., 1970), and in many other school, home and workplace exposures,

generally as case reports involving a few patients per report (Cakmak et al.,

2002) (Hodgeson et al., 1998) (Dales et al., 1991). These symptoms can occur in

all individuals with normal immunity because they are ultimately manifestations

of a robust immune response to a heavy unrelenting airborne fungal load with

consequential overload of clearing mechanisms or macrophages, and the activation

of inflammatory processes.

Although the general immune response to a heavy fungal antigen exposure may

consist of all the immunoglobulin isotopes (IgA, IgM, IgG, IgD and IgE) plus

sensitized lymphocytes or T-cells, specific IgG is the most efficient single

marker of generalized immune responses. Specific IgG antibody levels to fungi

are not diagnostic when taken alone. However, antibody levels to fungi are

directly proportional to levels of exposure in any individual, and generally

high exposure levels result in high antibody titers. These antibody levels drop

when the patient's exposure to the offending fungi ends. When elevated, they

are helpful in arriving at the presumptive diagnosis and repeat measurements at

four to six month intervals help verify compliance with the fungal avoidance

program and helps monitor the success of therapy.

A. Immune Complexes

The presence of antibody in the serum is not pathologic in itself. All the

immunoglobulins normally present in the tissues, with possible rare exceptions,

are antibodies and they contribute to the immune state. It is only when

antigen(s) combines with antibody(ies) that immune complexes are formed and a

potentially pathologic state is initiated. Immune complexes are not stable

since the union is one of complimentary surface configurational attraction

between two or more molecules produced by Van der Wall forces. The complexes

can easily be disrupted as the conditions in solution change. Changes in

temperative, relative numbers of reacting molecules, their nature, the epitope

specificity of the reacting antibodies, etc., can all effect changes in the

size, shape, surface charges, solubility, of the complex. These factors are the

ones that determine the inflammatory potential of the complexes formed and

whether the complexes will tend to be deposited in kidneys, joints, blood vessel

walls, skin, lungs, etc. (Cochrane et al., 1973). Because of the inherent

instability of immune complexes in tissue and serum, they are difficult to

study. Interest in understanding immune complexes was very high in the 1950's

and 1960's and quickly dissolved away when IgE was discovered (Ishizaka et al.,

1966) and the attention of the immunological research teams was attracted to the

newly defined antibody responsible for classical allergy symptoms, Type I of

Gell and Coombs.

There are sound scientific reasons why specific IgG antibodies to fungi are not

always diagnostic. Some individuals with high antibody levels to fungi remain

symptom free during re-exposure. Such individuals may be less likely to produce

the toxic immune complexes required to induce symptoms by virtue of the fungal

antigen epitopes to which they respond. They may respond to minor epitopes that

allow measurement of the antibody, but which do not engage in the formation of

toxic immune complexes. Other individuals may have a vast scavenger system,

which can rapidly take up and extinguish all immune complexes generated before

symptoms can ensue. Other individuals may satisfy the high exposure and the

appropriate symptom requirements and have relatively low total specific antibody

levels to fungi. They may be poor antibody responders with an even lower

capacity to deal with immune complexes. The observation that they can still

experience flu-like symptoms following fungal exposure demonstrates that a

relatively low antibody level can still produce significant, disabling symptoms.

Mold toxins can be powerful immune suppressors. It is sobering to remember

there would be no organ transplant program without the availability of fungal

toxins (e.g., cyclosporin). It is possible and even likely that the fungal

exposure of some patients will include exposure to immune suppressive

mycotoxins. Another cause for low antibody levels in a symptomatic patient

could be iatrogenic. Many patients develop arthritic symptoms and present

themselves to rheumatologists who may choose to use an immuno-suppressive drug

such as methotrexate to treat the arthritis. Such a drug will certainly depress

the immune response, relieve the severity of arthritic symptoms while masking

what could be the real trigger for the arthritis.

VIII. Therapy

The therapy of all hypersensitivity diseases must be based on avoidance. In the

case of fungi, it is important to recognize that there are three sources of

exposure: The airborne particles, mostly spores, which result from water

intrusion at home, school and work; ingestion as in the enormous amounts, and

types of fungal products used by the food industry; and colonization of skin,

lung, sinuses and other mucosal surfaces.

A. Environmental molds

A moldy environment must be remediated or destroyed. All sources of water

intrusion have to be discovered and sealed. All wetted surfaces must be

completely dried (e.g. both sides of sheet rock) and any surfaces showing fungal

proliferation must be replaced including walls, floors, carpets and pads,

cabinets, furniture, etc. In many cases of fungal hypersensitivity, the

affected individual may not be able to return to the remediated space because

his sensitivity is too great for the level to which remediation may reduce

fungal efflux. There is a simple canary-in-the-mine parallel. No amount of

surveying the remediated site can assure that the patient will be able to

tolerate the reduced fungal levels. More times than not, they cannot.

Avoidance may require a move to different quarters.

High efficiency particulate air filters (HEPA) are useful in removing spores

from the air. They remove a great majority of the particles greater than 0.3

microns in size, which includes all mold and bacterial spores. However, a

heavily mold-infested indoor space may overwhelm the ability of a HEPA room air

purifier to significantly reduce ambient spore levels. In some cases, ozone

generators have proven useful. They must be used at full power inside sealed,

vacant rooms for a full day to significantly reduce fungal growth. It is

important to stress that occupants should not be exposed to ozone, which is

toxic. The ozone is unlikely to kill spores or deeply situated mycelial

elements. Therefore, the process generally has to be repeated at least

bimonthly. The ozone levels achieved in the room may not be safe at any times

for individuals with asthma, chronic obstructive pulmonary disease (COPD) or

other forms of respiratory distress; but handling the ozoning process (i.e.,

initiating and terminating the treatment) is only slightly disagreeable to the

normal individual. Mold cells are similar to human cells in their makeup, which

means that ozone levels likely to kill mold cells are also likely to irritate

the human respiratory mucosa.

Food molds

Fungi are prolific enzyme and toxin generators, which is the basis for much of

their use in modern food technology. Bread will rise more quickly, require less

baking time and lower baking temperatures if amylase is added to the dough. The

amylase digests the cross linkages of the cellulose in the dough making it less

tough. This results in considerable economic gain for the baking industry. Its

downside is that it has produced substantial illness in bakers and it loads the

bread with mold products that add to the burden of a mold sensitive individual.

These additives are listed on the ingredient labels of breads as dough

conditioners or malted grains (for malt, read mold). Fruit juice manufacturers

discovered that if hemicellulases (of fungal origin) are added to the crushed

fruit prior to squeezing out the juice, the yield can increase as much as 25%.

The enzymes digest the cellulosic structure of the fruit and allow more juice to

be obtained from the cells. This is a wonderful economic gain for juice makers,

but adds fungal elements to the juice.

Citric acid is perhaps the greatest misnomer in the ingredients listing of any

food. It is added to most processed foods including soft drinks, jams and

jellies, frozen meals, etc. as a preservative. It conjures up visions of

lemons, oranges and limes. It is none of these; it is a direct product of

Aspergillus fermentation in commercial quantities. It is a highly impure

" citric acid " contaminated by many other Aspergillus products including toxins,

antibiotics, etc. One wonders if pure citric acid would confer the same

excellent preservative properties as commercial " citric acid " on foods? Again,

this is an excellent product for the food industry in extending the shelf life

of foods, but it adds fungal elements to the food.

Some foods are obligate products of fermentation such as aged cheese (usually

Penicillium), soy sauce (usually Aspergillus), chocolate (mixed molds), and

black tea (Aspergillus). While wonderful on the educated palate, they must be

eliminated in a mold-free diet. The patient trying to avoid mold in his food

must be instructed in how to maintain a fresh food diet. This means shopping

more frequently than weekly. Farmer's markets are often excellent sources of

fresh fruits and vegetables. This may be especially difficult in small towns

where the supermarket is the only source of food.

C. Colonization

Colonization of the human mucosa is a common phenomenon that seems to be poorly

understood. The human body is colonized by bacteria in the nasopharynx, mouth,

gastrointestinal tract, skin, etc. No one questions this and the concept of a

balanced ecology in the gut is considered essential for proper gastrointestinal

(G.I.) function and a stable supply of nutrients such as vitamins. Fungal

colonization is also a widely accepted phenomenon, as for example, toenail

fungus, athlete's foot, vaginal candidiasis, chronic fungal sinusitis and

seborrheic dermatitis. But the concept that fungi can become part of the normal

mucosal flora, and that once established, fungal colonization can place a heavy

burden on the body's defenses is not always appreciated. Some fungi produce

toxins and all fungi produce and secrete enzymes into their environment. The

body has to protect itself against all foreign proteins, especially those that

carry enzymatic activity. The immune response is that protection. Foreign

enzymes are known to be among the most powerful stimulants of an immune response

(Larson et al., 1996).

Patients who have become ill from living or working in a moldy space are often

improved when they move, but their health does not always return to normal.

This means either that the fungal exposure resulted in permanent damage, which

is quite possible with tissue deposited immune complexes or certain mycotoxins,

or there is continued exposure to the fungus because of colonization.

Colonization is more likely to occur first where there has been previous tissue

damage. The nasopharynx is the first filter for airborne fungi and would expect

to be first to be colonized along with adjacent communicating structures like

the sinuses or middle ear. Colonization is more likely to occur where there are

residual scars from past disease or surgery. This is where the body's first

line of defense, mucous flow, ciliary action and IgA secretory antibody function

is likely to be missing. The lungs are easy targets for colonization when there

has been previous damage as in a past pneumonia. Children with cystic fibrosis

are virtually 100% colonized in the lungs (Etzel et al., 1998) and patients with

chronic asthma are said to be about 30% colonized. The esophagus is a common

site for colonization because of its vulnerability to damage from hot foods,

spicy foods and acid reflux.

D. Antifungals

When possible, colonization is best treated topically. The oral cavity and

esophagus can be treated with liquid fluconazole (40 mgm/ml) or Itraconazole,

(10 mgm/ml), 40 or 50 mgm four times daily. Neither of these is well absorbed

in a non-acid media and they can be quite effective topically until they reach

the stomach where they may be absorbed. Nystatin is a non-absorbed antifungal

with an excellent safety record. It can be given as a powdered suspension in

water at 500,000 units four times daily. It will continue to provide antifungal

activity throughout the G.I. tract, as it courses its way from mouth to anus.

Fungal colonization of the nasopharynx, sinuses and middle ear is best treated

with an antifungal nasal spray. A 2% ketoconazole suspension or a 0.01%

amphotercin B solution applied generously four times daily to the nose is

effective in many cases. It must be delivered deep into the nasal cavity and be

felt passing into the pharynx. Neither will be significantly absorbed in the pH

neutral mucosa of the nose. The benefits of therapy are likely to be noted

within a few weeks but a cure, where therapy can be safely stopped without

recrudescence of the illness, is months and sometimes years in the future. This

is likely due to the resistance of the spore to killing with available

antifungal drugs which means that therapy must be continued until all spores are

eliminated or germinate and become susceptible to the action of the antifungal.

Colonization of the lungs and sometimes the sinuses requires a systemic

antifungal such as Itraconazole, ketoconazole or voriconazole. Each are given at

200 to 400 mgm per day (Schubert, 2000) (Gallin et al., 2003). In some cases of

lung disease a nebulized antifungal is helpful. Ketoconazole has been

successfully used nebulizing 50 mgm per treatment, twice daily.

Many physicians show great concern when talking of systemic antifungals because

of the possibility of liver damage. This concern is grossly overstated. Most

antifungals used in high doses are given to immunocompromised individuals with

severe fungal infections including blood-borne dissemination. Elevated liver

enzymes in such catastrophic illness is not rare and must be considered in the

decision to use such therapy. However, in my ten-year experience with

antifungals in immunologically normal individuals colonized by fungi, I have yet

to see a single episode of elevated liver enzymes, which can be attributed to

the use of the antifungal. Testing for liver function at two to four month

intervals is recommended by the FDA. It has been reported that in those rare

instances where liver enzymes have risen, cessation of therapy results in a

rapid return to normal in all but a few rare instances. The antifungals are

metabolized in the liver and place some burden on the detoxification enzymes of

the liver, which are also used to metabolize certain drugs. The use of

antifungals may influence the serum and tissue levels of such drugs generally

causing a rise in concentration as the rate of metabolism of the drug is

reduced. Such changes can be handled by careful assessment of tissue levels of

drugs used simultaneously with the antifungals.

Fungal colonization of the G.I. tract is a relatively common phenomena

encouraged by the over use of antibiotics in medicine and their use in the

production of meat for human consumption. This usually manifests as abdominal

discomfort, heartburn, increased gastric emptying time, bloating, crampy

abdominal pain and increased transmucosal uptake of large food protein molecules

(leaky gut). Treatment is best begun with a non-absorbed antifungal such as

Nystatin or poorly absorbed antifungals such as miconazole or econazole.

Nystatin is best given as a powdered suspension, two to three million units per

day in divided doses (bid or tid). The miconazole and econazole are not

generally available in pure powder form from regular pharmacies and must be

formulated. This increases the cost somewhat but still leaves them far cheaper

than the newer antifungals already mentioned. They are given in 250 mgm

capsules twice daily.

1. Jarisch-Herxheimer Reactions

The treatment of fungal colonization in patients hypersensitive to fungi almost

always produces a Jarisch Herxheimer (JH) reaction if given too aggressively.

It is safest to begin with one quarter or less of the therapeutic target dose

and advance every three to four days in doubling doses to those reach the

desired dose. The JH reaction can occur at the initial dose or at any time the

dose is increased. It manifests as a flu-like reaction in its broadest sense,

i.e., headache, rash, low grade fever, myalgia, arthritis, night sweats,

malaise, cough, diarrhea, etc. When it appears, treatment should be stopped

until the symptoms disappear (usually one to two days) and then a lower amount

should be introduced and held there for two weeks before any attempt to increase

the dose. It is best to be guided by the patient who quickly learns if there is

a limit to the dose he can tolerate, but he may subsequently have to be

encouraged to try to take more medicine if past experience(s) has been severe

enough to be alarming. The JH reaction can also occur when the patient who is

seemingly stable (on full dose), suddenly experiences a larger fungal burden,

such as in staying in a moldy hotel room on a trip or following a day of

spreading compost in a vegetable garden.

Colonization of the skin in the form of abscesses on the skin or dry scaly

rashes over the palms of the hands (dishydrotic eczema) can be treated with

topical antifungal creams, sometimes coupled with systemic antifungals. The

topical antifungal action on the skin can be enhanced by use of occlusive

dressings. Patients are directed to apply the cream liberally at bedtime and

then cover the lesion with a watertight membrane (e.g., plastic food wrap) which

remains overnight.

All fungal therapy must be prolonged, often for a year or longer. This is

likely due to the resistance of fungal spores to any medicine and the rapid

reestablishment of colonization, should therapy be ended too soon. All the

spores must have been shed or have germinated and been killed by the action of

the antifungal and the body's natural defense system before the colonization is

truly ended.

IX. Conclusion

The best treatment for health problems arising from exposure to high fungal

levels is prevention. A key prerequisite to prevention is education.

Information about the nature of fungi, their presence in foods, their rapid

proliferation after water intrusion in homes, workplaces and schools, and their

potential for health effects must be made easily available to the general

public. The Internet has already provided such information to millions who use

computers. Insurance companies are excluding mold damage from the coverage

provided in homeowner policies and this may alert the homeowner to the danger

and to his/her responsibility to move rapidly to minimize the effects of water

leaks. Reports in the media of litigation by celebrities experiencing fungal

illness, also helps increase public awareness of the problem. Public health

service organizations have to date been more concerned to quell the public's

concern about mold problems by suggesting that it is not an important issue.

This is a disservice. It would be far better to acknowledge the potential

health effects of mold exposure along with suggestions for controlling mold

levels in homes, workplaces and schools.

Acknowledgments

The author is grateful to his daughter, Tess Marinkovich for critical reading

of this manuscript and to Borch for her help in preparing the text.

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PAGE 31

January 14, 2010

Thank you for posting this

From: carondeen <kdeanstudios@...>

Subject: [] Re: Dr. Marinkovich paper on use of anti-fungals

Date: Thursday, January 14, 2010, 9:12 AM

Fungal Hypersensitivity: Pathophysiology, Diagnosis, Therapy

I. Introduction

The comments contained herein are

January 31, 2010

Who took this Doctors place??

In a message dated 1/31/2010 6:18:41 P.M. Central Standard Time,

tug_slug@... writes:

, that was an excellent article, to bad my GP hasnt read it.

>

> Fungal Hypersensitivity: Pathophysiology, Diagnosis, Therapy

>

> I. Introduction

>

> The comments contained herein are those of a clinical immunologist whose

major professional activity is patient care. Over the last several years

as the general awareness of fungal exposure as a cause of illness has grown,

more and more patients have been presenting themselves for diagnosis and

treatment after exposure to homes and offices heavily contaminated by fungi.

The Internet has come to play a major role in the dissemination of good,

and some not so good, information about fungal diseases and the number of

patients has mushroomed. Most American trained physicians have had little

instruction in mycology and tend to dismiss or minimize the possibility of

fungal illness except for certain generally accepted special situations. These

would include immunologically deficient patients, Candida infections in

women, thrush in newborns, skin infections such as ringworm and athlete's

foot, and lung infections in areas endemic for histoplasmosis or

coccidioidomycosis. E ven allergists who limit themselves to skin tests for

diagnosing

hypersensitivity ignore patients complaining of serum sickness like symptoms

(e.g. headaches, rash, malaise, joint pain, etc.) following exposure to

moldy environments and often refer them for psychiatric care (Terr, 2001).

The unfortunate patient has nowhere to turn except to those few physicians who

have listened to their patients, believe what they say and accept the

challenge to try to help. These physicians have gone to the Internet or the

medical literature and developed scientifically inspired diagnostic and

treatment programs that have proven to be helpful to their patients. I stand

among these physicians and I would vigorously defend the scientific basis and

efficacy of my approach to the diagnosis and treatment of patients suffering

from exposure to high ambient levels of fungi in indoor environments. My

best thoughts on the subject are offered herein.

>

> II. Health Effects of Fungi

>

> There is

January 31, 2010

, that was an excellent article, to bad my GP hasnt read it.

>

> Fungal Hypersensitivity: Pathophysiology, Diagnosis, Therapy

>

> I. Introduction

>

> The comments contained herein are those of a clinical immunologist whose major