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.
B. 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.
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.
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.