Abstract: Ten randomly selected patients with recurrent nonspecific small vessel vasculitis (edema, petechiae, spontaneous bruising, peripheral cyanosis) were studied under rigid environmental control. All cleared their symptoms without medications. All patients had their vasculitis reproduced after direct challenge with numerous individual foods and chemicals. Multiple incitants were found in each patient.

Detailed lifelong ecological histories were taken by Randolph=s¹ method, searching for other parts of the environmental maladaptation syndrome. Specific symptom complexes and recurrent inflammation such as sinusitis, laryngitis, hoarseness, bronchitis, cystitis, spastic colon, enteritis, colitis, migraine or vascular headaches, myalgia, arthritis, arthralgia, depression, cardiac arrhythmia or phlebitis of unknown etiology were recorded.

An attempt was made to create an environment that was as free as possible from inhaled and ingested contaminations and where triggering agents could be clearly defined. Thus, cause and effect could be established.

Rooms were specially constructed. Walls were made of glass and cement blocks. The blocks were painted with a low outgassing paint that was allowed to dry from six months to one year so as to eliminate any volatile petrochemicals. Floors were of stone (terrazzo) or hard vinyl (also allowed to age). Ceilings were of mineral rock. Lighting was fluorescent, hanging from the ceiling, with metal shades. Beds and furniture were all metal or hard wood and void of volatile plastics. Mattresses were of chemically less treated 100% cotton with all the plastic removed. All bed linen and curtains were chemically less contaminated 100% cotton that had been laundered in pure nondetergent vegetable or animal soap. The heat and air conditioning were local electric, using air blown over steel coils containing water. Filters of activated charcoal and alumina-oxide impregnated with potassium permanganate were placed at the entrance to rapidly eliminate extraneous fumes, odors, and particles that might come through the doors. No offensive synthetic or natural odors were allowed in the rooms. The rooms were as totally devoid as possible of volatile petrochemicals and dust, as judged by susceptible humans acting as monitors and as registered on the synthetic odor detector. No smoking was allowed. Rooms were cleaned with borax, nonchlorinated cleaner, and water.

All patients, during the course of diagnosis and treatment, were kept in the rooms for at least a 16-day period. Patients were required to remove all hair sprays, cosmetics, perfumes, and polyester clothing before entering the room and to wear chemically less treated 100% cotton. Upon entering the room, patients stopped all medications, including anticoagulants and steroids. Once the patients reached the symptom free basal state, they could act as their own controls. No medications were given during the stay in the unit with the exception of oral or intravenous bicarbonate of soda and oxygen. Pulses, blood pressure, temperature, bruising, petechiae, and color changes were monitored every four hours. After the patient was in a basal state free of signs and symptoms, including absence of petechiae and bruises, with normal pulses and a rate below 80, able to sleep all night and had lost his hunger, challenge with single chemically less contaminated source food (an individual pure food whose origin is known, i.e., wheat, oats, cane sugar, beet sugar, chicken, duck, turkey, etc.) was begun. The food was selected individually and randomly. In order not to miss delayed reactions, no more than four source foods were tested in one 24-hr period. As many as 60 individual source foods were tested sequentially during the period in environmental control. Pulses were recorded five minutes before and at 5-, 20-, 40-, and 60-minute intervals after meals. Electrocardiograms were taken with the onset of any arrhythmia. The time of onset after the challenge was noted. All signs and symptoms were recorded. Testing of the next food was not begun until all previous reactions had subsided.

After totally tolerated foods were found the patients were retested with these same nonreactive foods but this time obtained from the commercial market. The commercial foods were naturally contaminated by synthetic sprays, herbicides, preservatives, artificial colorings and sweeteners, wax and plastic wrappings, or other additives occurring during their production and processing. These were cooked on gas stoves in synthetic cookware. Individual and cumulative reactions from one to six consecutive meals were observed and recorded.

Testing of odors was done in the following manner: Each patient was given a timed exposure of one to sixty minutes to the flames of natural gas, cigarette smoke, chlorine, perfume, pine-scented floor wash, ethyl alcohol, formaldehyde, phenol, and pesticides. In addition, challenge to the fumes of common odor producing material such as home carpet, foam pillows, polyester clothes, which the individual breathed daily in the home and work environment, was done. Each exposure was at a distance of 20 inches with a constant flow of the vapor. All odors tested were of a double-blind nature in that neither the examiner nor the patient knew the content of the container until after the test. Saline was used as a control.

The following laboratory tests were performed. Complete blood count, sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, serum protein, protein electrophoresis, immunoglobulins (IGE, IGG, IGA, IGM), total hemolytic and serum complements (C₃ and C₄), prothrombin time, partial thromboplastin time, platelets, Lee and White clotting time, calcium, phosphorus, fibrinogen, fibrinolysins, fibrin split products, glucose, uric acid, alkaline phosphatase, serum glutamic oxalo-acetic transaminase, lactic dehydrogenase, alpha 1 antitrypsin, and C₁ esterase inhibitor were obtained upon entrance into room and at the beginning and end of testing. C₃ and C₄ were done daily during the period of fasting. Biopsies were taken of the spontaneous bruises and petechial hemorrhages.
 
 

After testing started, it became quite obvious that reactions fell into three categories. The first consisted of unmistakable signs, such as rhinorrhea, nasal stuffiness, hoarseness, cough, wheezes, peripheral blanching, cyanosis, swelling or loss of pulses, bruising, polyuria, fever, increased pulse rate, blood pressureCdecreased or elevated, arrhythmia, petechiae, bruising, and phlebitis. The second category consisted of equivocal signs and the third category of no observed reactions. The latter two were lumped together for statistical purposes and considered as having no observed reactions.

All ten patients clearly had their vasculitis reproduced on at least three separate occasions. Usually, there was a sequential progression of symptoms of color change of the hands, feet, nose, and skin followed by pulse alteration, periorbital and peripheral edema, petechia, and/or spontaneous bruising. It is evident by the data shown in Table II that many different susceptibilities existed in each patient. Also, it was observed that some individual incidents would produce only portions while others would produce all the patient=s original signs and symptoms. These reactions were further substantiated by the benign asymptomatic course after ingestion or inhalation of nonreactive foods and food odors plus the reproducibility of signs by retesting of reacting foods. Of the reactions that occurred within the first four hours, 95% started within the first five minutes after ingestion, leaving no doubt in the minds of observing personnel and patients that there was a cause and effect relationship. The severe reactions lasted up to 48 hours with lesser effects lasting up to five days. The moderate reactions lasted four to eight hours while the mild ones were terminated within a four-hour period. Of the associated signs and symptoms, 100% were reproduced.

All reactions to inhalant chemicals were within the first one and a half hours and their after-effects lasted up to 48 hours although most terminated within a four-hour period. Ten patients reacted to the fumes of the flame of the gas pilot, reproducing assorted signs and symptoms in all patients and reproducing the vascular signs in six. The most striking examples were those of 33-year-old and 34-year-old females who had a 15-second exposure to the natural gas pilot. Patient A developed immediate dizziness, staggering, and then premature ventricular contractions followed by severe leg pain and bruises over both extremities. Recovery took 36 hours. Patient B developed immediate abdominal cramps, irritability, chills, and vascular spasm of hands and feet vessels followed by spontaneous bruising and depression. Recovery took 48 hours under oxygen with the patient writhing in pain and complaining of abdominal cramps most of this time.

Double-blind exposures to the various inhaled chemicals are seen in Table III. One can see the widespread involvement of susceptibilities to these chemicals. Not shown is the fact that the transient exposures produced spontaneous bruising in all patients at least on two different occasions. Vascular spasm with cyanosis was seen in all patients frequently, as were petechiae and periorbital edema.

In viewing the life-long histories it is difficult to say when the vasculitis started. However, several facts were evident. Most patients had symptoms due to abnormal responses to environmental stimuli in early childhood. These increased insidiously over many years before exhibiting the full vasculitis syndrome. Many could clearly relate accentuation of their allergic manifestations with apparent spreading of intolerance to commonly used foods and outgassing objects such as newsprint, perfume, plastics, etc. very early in life. Frequently, precipitating overexposure episodes such as having the house fumigated would trigger the cascade of spreading intolerance to both foods and chemicals. This spreading phenomena seemed to occur in patients with a background of susceptibility though two patients on careful scrutiny were totally asymptomatic at the time of the precipitating exposure. A careful review of the clinical course in these patients revealed three or four of the smooth muscle systems to be involved, indicating widespread disease. This multisystem involvement clearly distinguishes the patient with environmentally triggered disease from the average atopic patient. Even though the patients presented with multisystem complaints due to apparent spreading of intolerance many isolated clues were present years before the onset of the vasculitis. Ninety-plus percent had tonsillectomies, indicating involvement of the respiratory and immune systems in early childhood and even infancy, thereby pointing out the importance of obtaining this information early in life. Family histories were also very important in that 60% had ancestors who suffered and eventually died from a nonarteriosclerotic cardiovascular entity. Finally, most patients had isolated chemical intolerance with years of complaints of a hypersensitive sense of smell to these. Usually, odors of various chemicals such as chlorine, newsprint, fabric stores, pesticides, etc. would cause them to be nauseated or ill. All gave histories of being able to smell natural gas when others could not.

Water quality apparently plays a significant role in the development and treatment of vasculitis. Eighty percent of the patients in this series were tried on at least four different nonchlorinated spring and filtered waters before their symptoms cleared. One hundred percent of the patients reacted strongly to a blind challenge of chlorinated water. It repeatedly became apparent that use of well water was hazardous due to wiidespread permeation of the water table with pesticides. As pointed out by Randolph,¹⁰ the patient=s water intolerance must be solved or symptoms will not clear and other testing results will be suspect.

Food as a trigger to pathological responses has been mentioned by past generations of food allergists. Its importance in the pathogenesis of disease has been overlooked recently. Responses to food testing have frequently been confusing for numerous reasons, including alteration of reactions by extraneous environmental insults and the so-called delayed food reactions. Apparently, food reactions in susceptible individuals are influenced by many factors, including the quantity and frequency of ingestion, temperatures of the foods, multiplicity of ingested synthetic elements in the food, the ambient inhaled air quality including temperature, humidity, barometric pressure, amount of ionization, the number and type of pollutants, the quality of ingested water, cyclical hormone influences and the state of nutritional balance of the individual. This complexity explains why few triggering agents have previously been found with certainty. The controlled environment decreases the complexity and adds to the clear definition of foods as one facet of the triggering agent for vasculitis and possibly many other diseases of unknown etiology.

In a controlled environment it becomes clear that most food reactions are immediate rather than delayed. However, many reactions are insidious and start with relatively minor symptoms such as transient nasal stuffiness, malaise, hoarseness, depression, or belching. Later, they frequently crescendo into devastating symptomatology. Once the physician and patient observe this sequential phenomena under controlled conditions, they are able to dissect out other influential environmental triggering agents.

The increase in the ambient air pollution further adds to the difficulty of defining triggering agents. There appear to be two types of effects from inhaled pollution. One is an overall depressant effect which is very subtle. This appears to be a volume load effect and may account for the fact that certain symptoms are accentuated in days when there is more air pollution with all other facets remaining constant. These observations were first observed by Randolph¹¹ and were later supported by analytical studies of ambient air by Whitby et al.,¹² who measured air in various areas of the world. They found that sea air had the fewest fumes and particles (excluding salt). Comparable standards for clean continental air showed a tenfold increase in pollution while air blowing from cities, but still on continental areas, increased pollution at least 35 times. The city on a good day had 150-fold more pollution while on bad days it increased 1,000 to 4,000 times. The abnormal responses of patients to food in this series were more frequent and accentuated when they were taken out of the environmental control unit to areas of higher nonspecific air pollution. This was further evidenced when the same patients went to areas of the country with less air pollution and found reactions to certain foods to be much less or even absent in a few instances. With less ambient air pollution they also found ingested chemicals, formerly intolerable, to be less harmful. Because of this effect, it became clear that patients had to have 10 to 12 hours in a less polluted environment to keep their vasculitis under control out of the hospital. This necessitated cleaning up the home by removing the high outgassing plastics (polyvinyls, polyethylene, polyurathane, foam rubber, etc.) and other synthetics (oil base paints, natural gas, etc.) as well as eliminating particle producing materials. Most of all, none got well until their natural gas appliances, including heating, were removed.

While developing instrumentation for the orbital space laboratory Poehlmann et al.¹³ observed that the fine tuning of instruments was initially distorted, giving disastrous results. They measured outgassing potentials of all materials and found glass, steel, metal, and stone to be inert while the soft plastics, such as polyvinyl chloride, polyethylene, polyurethane, and silicone, to be constantly fuming. Some of the hardest synthetics like masonite, polycarbonate, and Formica had initial fuming but little thereafter. Knowledge of these phenomena is crucial in diagnosing and treating a chemically susceptible vasculitis patient. This nonspecific pollution effect usually explains why patients are not clearing all symptoms periodically and also explains sudden susceptibility to formerly safe foods.

The second type of response to air pollution followed the more classic allergic reactions with a sudden precipitating onset followed by the usual sequence of symptoms. This was also present to the same incitants and was easily reproducible. In addition to occasional pollen, dust, and mold triggering incitants were mainly due to halogenated petrochemicals such as pesticides, floor cleaning compounds, and/or metals like copper, aluminum, cadmium, and nickel. This effect was always most evident if the patient=s ambient overall pollution level was low.

Environmentally triggered small vessel vascular disease is probably part of a spectrum of inflammatory diseases of all sizes of arteries since smooth muscle appears to be the sensitized system involved. This particular group of patients had blood vessel involvement at the precapillary arteriole level and/or small arteries of the intra-organ type. At times, there were large vessel responses but minimal in this group of patients.

Laboratory data were unremarkable other than the change in the serum complements. Immunoglobulins were not elevated and did not change much. The fact that patients did have immediate type I reactions (Gell & Combes) with some challenges makes one suspect that there was alteration of IGE at the local level. However, as shown recently in allergic lung diseases this response may be more a reflection of IGG alteration.¹⁴ Direct triggering of the kinin and complement systems bypassing the a-a reactions also apparently occurs. The complement mechanism is involved in producing the inflammation, since all patients had mild depression of the C₃ and some elevation of the C₄. It would have been interesting to measure kinin levels, but these were unavailable in our laboratory at the time of these studies. Many of the clinical characteristics in this series are similar to those of Garner and Diamond,¹⁵ who found kinin elevation associated with bruising but thought the triggering was due to autoerythrocyte sensitization, and by Leibe,¹⁶ who actually introduced bruising by kinin injection in a single patient.

The intrinsic mechanism of the environmentally triggered arteritis is unclear but probably encompasses a variety of mechanisms. Some incitants probably trigger the deposition of antigen-antibody complexes in the vessel walls. Another possible mechanism which occurs in other vasculitis would be the alteration of a native component of the vessel so that it becomes antigenic and induces hormonal or cellular immunity. Deposition of an antigenic foreign substance within the vessel should also be considered in some patients. Finally, an alteration of a vessel wall component so that it directly induces an inflammatory response surely occurs in other patients. Regardless of these different pathways for the final production of vasculitis, it is now possible to define a multiplicity of incitants in any given patient, thus allowing us the opportunity to remove the triggering agent.