Environmentally Triggered Thrombophlebitis

William J. Rea, MD
 
 

Source: Annals of Allergy, 37(2):101-109, Aug. 1976.

Abstract: Ten randomly selected patients with recurrent nontraumatic thrombophlebitis of unknown etiology were studied using a comprehensive environmental control method. All cleared their phlebitis without medications. Using withdrawal and challenge of incitants, eight of 10 patients had their phlebitis reproduced. The numerous single triggering agents were commonplace inhaled and ingested foods and chemicals. Supported by the Human Ecology Research Foundation of the Southwest.
 
  The growing concern for the role of environmental factors in the pathogenesis of human ills presents new challenges to the clinical investigator. It allows us to re-examine diseases of unknown etiology in a new light. It has been well shown that a combination of various degrees of venous stasis, hypercoaguability of the blood and endothelial irritation1 is the pathophysiology behind venous thrombosis. The actual triggering agents of the phlebitis are rarely known.2 Advances in the knowledge of the specific immunoglobulins, complement, kinin, fibrinolytic interactions including endothelial irritation, thrombosis triggering, and increased membrane permeability has led to the obvious conclusion that phlebitis and immune response are intimately related. The development of comprehensive environmental control3 has allowed us a useful tool to study this dangerous disease with safety under controlled conditions.
 
  MATERIALS AND METHODS Ten randomly selected patients from the author=s cardiovascular surgical practice (nine females and one male), ages 26-66, with recurrent nontraumatic thrombophlebitis and pulmonary embolism of unknown etiology were studied. Detailed lifelong ecological histories were taken by Randolph=s method,4 searching for other parts of the environmental maladaptation syndrome. Specific symptom complexes such as recurrent sinusitis, colitis, cystitis, bronchitis, laryngitis, pharyngitis, spastic colon, enteritis, migraine or vascular headaches, vasculitis, myalgia, arthritis, arthralgia, depression and cardiac arrhythmia with unknown etiologies were recorded.

A chemically less contaminated environment was created for study of these patients. 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, from the ceiling, with metal shades. Beds and furniture were all metal, wood, and void of volatile plastics. Mattresses were of chemically less treated 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 eliminate rapidly extraneous fumes and odors that might come through the doors. No offensive synthetic or natural odors were allowed in the rooms. The rooms were as totally void 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.

Food used for testing was grown, transported, stored, and prepared in the relative absence of petrochemicals. Only natural fertilizers were used to grow the food and no insect sprays, herbicides, or preservatives were used. Storage was in glass jars or nonpetroleum-based cellophane bags. Preparation was in glass or stainless steel utensils, heated by electricity. The eating utensils were glass or stainless steel and the drinking water was filtered with activated charcoal so as to remove chlorine and pesticide residues.

 All patients during the course of diagnosis and treatment were kept in the rooms for at least a 16-day period. All 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 and as soon as the venograms were done, patients stopped all medications, including anticoagulants. 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. Pulse, blood pressure, temperature, leg size and tenderness were monitored every four hours. After the patient was in a basal state free of signs and symptoms, including calf tenderness, pulse below 80, able to sleep all night, and had lost his hunger, challenge with single chemically less contaminated source food was begun. (Source food is an individual pure food whose origin is known, i.e., wheat, oats, cane sugar, beet sugar, chicken, duck, turkey, etc.) The food was selected individually and randomly. No more than four source foods were tested in one 24-hour period. As many as 30 individual source foods were tested sequentially during the period in environmental control. Pulses were recorded five minutes before and 20, 40, and 60 minutes after meals. Electrocardiograms were taken with the onset of any arrhythmia. All signs and symptoms were recorded. Testing of the next food was not begun until all 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 to a range of 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 60 minutes to the flames of natural gas, cigarette smoke, perfume, pine-scented floor wash, and ethyl alcohol. Common chemicals such as home carpet, foam pillows, polyester clothes, etc., which they breathed daily in the home and work environment, were also tested. Each exposure was at a distance of 20 inches with a constant flow of the vapor.

The following laboratory tests were performed: CBC, 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 oxaloacetic transaminase, lactic dehydrogenase, alpha 1 antitrypsin and C1 esterase inhibitor were obtained upon entrance into the room, at the beginning and at the end of testing. C3 and C4 were done daily during the period of fasting.

As a definitive test to assess the complete absence of phlebitis or even mild residual venous sensitization, the following procedure was done on each patient. All were required to walk without stopping 10 times the distance they could prior to entering the unit. Each was requested to ride an exercycle against a resistance of at least 150/kg/m before and after the period of detoxification. (None could ride before detoxification.)
 
 

 RESULTS As shown by Table I, there was an impressive number of associated signs and symptoms related to the environmental maladaptation syndrome occurring during the patient=s lifetime. Each patient averaged more than ten distinct recurrent signs and symptoms. Sixty-five separate episodes of phlebitis required hospitalization while the numerous episodes of chronic leg pain treated at home were incalculable. Twenty-two distinct episodes of pulmonary embolism, confirmed by lung scan or pulmonary angiogram, were present. Many minor episodes of chest pain and shortness of breath, characteristic of emboli, occurred but could not be substantiated by laboratory data as definite emboli.

Table 1

Associated Signs and Symptoms
Tonsillectomy
10
Recurrent spontaneous bruising
10
Recurrent nasal stuffiness
10
Cold susceptibility
10
Increased sense of smell
9
Adult acne
8
Recurrent myalgia
7
Recurrent sinusitis
6
Recurrent headaches
6
Spastic colon and/or nonspecific colitis
5
Recurrent nonspecific chest pain
5
Recurrent bronchitis or bronchopneumonia
5
Recurrent overwhelming fatigue
5
Extremity vascular spasm
5
Recurrent sore throats
4
Asthma
4
Recurrent arrhythmias
4
Recurrent cystitis
4
Recurrent depression
2

  Nine of 10 patients had been on Coumadin for at least two years, with one of these patients also being on Persantin. The tenth patient had been on beef heparin for one and a half years (Table II).

Table II
 

Anticoagulant
Pulmonary Embolus
Episodes of Phlebitis
Caval Interruption
1. 33 WF
C
3
20
+
2. 26 WF
C
3
8
+
3. 55 WF
C
0
2
0
4. 44 WF
C
4
5
+
5. 53 WF
H
4
10
+
6. 39 WF
C
0
6
0
7. 52 WF
C
3
4
+
8. 65 WM
C
3
1
+
9. 33 WF
C & P
0
3
0
10. 50 WF
C
2
8
+

  All 10 patients, once under environmental control, cleared their active symptoms, including their ongoing phlebitis, in three to 10 days. However, the symptoms were frequently accentuated for the first two to three days. Most patients underwent withdrawal exactly as Randolph described in his chronically ill patients. Each patient initially had hunger followed by complaints of Anervousness,@ Ajitters,@ and headaches. There were observable signs of agitation, trembling, and depression. Insomnia was the rule the first night, which was followed by diarrhea in five patients. Complaints of generalized muscle and joint aches occurred and were accompanied by sensitivity to touch of the affected muscles. Initially, there was tenderness along the course of the saphenous or deep veins, followed by gradual diminution and finally elimination of this tenderness. As the patients became asymptomatic, all stated that they had not felt that well in years. This feeling of well-being was confirmed by observable signs of animation, walking, even riding a stationary bicycle (which none had previously been able to do). Ten patients were able to walk a distance of 10 times their pre-environmental control experience. All 10 patients then rode the bicycle at least six miles a day against a resistance of 0-150/kg/m. All calf tenderness and positive Homan=s signs were gone.

After testing started, it became quite obvious that the reactions fell into three categories. The first consisted of unmistakable signs such as cough, rhinorrhea, scratching, diarrhea, wheezes, hoarseness, edema, calf tenderness, bruising, polyuria, fever, increased pulse rate, blood pressure decrease, watering eyes, nasal stuffiness, belching, skin rash, cyanosis, decrease in peripheral pulses, arrhythmias 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.

Eight of 10 patients clearly had their phlebitis reproduced on at least three separate challenges. It is evident from the data shown in Table III that many different susceptibilities existed in each patient. Also, not shown in the table, is the fact that some individual stimuli would produce only portions of, while others would reproduce all of, the patient=s original symptoms and signs. These reactions were further substantiated by the benign asymptomatic course after ingestion of nonreactive foods or inhalation of food odors and the reproducibility of signs by retesting of reacting foods. One hundred percent of the reactions of chemically less contaminated food started within four hours of ingestion and no new test was performed until the patient was without signs and symptoms even though some reactions lasted for 48 hours. Ninety percent of these reactions started within the first 15 minutes after ingestion, leaving no doubt in the minds of the observing personnel and patients that there was a cause and effect relationship. One hundred percent of the patients= associated signs and symptoms were reproduced.

Table III
 

Offending Agents

 Associated Signs & Symptoms Reproduced Phlebitis Reproduced
1
 Beef, chicken, cigarette smoke, shrimp, pork, gas heat, ingested chemicals Diarrhea, pulse increase 30 b/m, nasal stuff, bigemeny, multifocal PVC=s Pork, shrimp, inhaled chemicals
2
 Wheat, rice, inhaled chemicals Vomiting, pulse increase 40 b/m, catatonia No
3
 Corn, cane sugar, eggs, inhaled chemicals Wheezing, rhinorrhea, red nose, nasal stuffiness, tender muscles, cystitis Corn, eggs, inhaled chemicals
4
 Beef, potatoes, corn, ingested chemicals Peripheral pulse from 4 to 1+, tachypnea, S.O.B. cyanosis, belching Beef, corn, ingested chemicals
5
 Pork, pork fumes, ingested chemicals, inhaled chemicals EdemaCgeneralized, tender muscles, colitis, dizzy Pork, cane sugar, inhaled chemicals
6
 Legumes, seafood, cane sugar, wheat, chicken, cigarette smoke, ingested chemicals, inhaled chemicals P. 35, syncope, wheezing, muscle tenderness, hives, paroxysmal atrial tachycardia Cigarette smoke, ingested chemicals, inhaled chemicals, seafood
7
 Beef, chicken, lettuce, ingested chemicals, inhaled chemicals GI bloat, belching, diarrhea, PVC=s, ventricular tachycardia Wheat, potatoes
8
 Turkey, chicken, peas, beef, cigarette smoke, inhaled chemicals Decrease in pulse left arm only, left neck and arm tenderness, tender over arm veins No
9
 Coffee, peanut butter, cane sugar, ingested chemicals Dyspnea, wheezing, eyes watering, hoarse, pulse increase 50 b/m Apples, corn, wheat, inhaled chemicals
10
 Corn, wheat, beef, eggs, inhaled chemicals Cystitis, diarrhea, skin rash, itching, dyspnea, pulse increase Chicken, beef, inhaled chemicals

  Testing for ingested chemicals resulted in symptoms and signs after the initial meal in six patients while the remaining four patients took from two to six meals to produce signs.

All reactions to inhalant chemicals were immediate and their after-effects lasted up to 48 hours, although usually terminated within a four-hour period. Nine of 10 patients reacted to the flame of the gas pilot-light, reproducing associated signs and symptoms in all and phlebitis in six patients. Challenge with perfume produced recognition and repulsion in 10 patients. Resting the back of the head on a foam rubber pillow caused rhinorrhea, nasal stuffiness and red nose in 10 patients. Other reactions included headaches, muscle aches, and leg pains. Test exposure was stopped at the point of reaction. Symptoms were totally relieved in one-half hour after removal of the foam rubber from the unit and replacement with the pillows of untreated cotton. Cigarette smoke caused not only recognition, but withdrawal and repulsion in 10 patients because of its irritating effects. Challenge with ethyl alcohol gave a similar response, including two patients who also complained of nausea and headaches. The most dramatic responses were in two totally asymptomatic patients who were given a 15-second exposure to common floor wash chemicals and gas pilot-light on separate occasions. They immediately developed hoarseness, wheezing, and then phlebitis, the timed progression being as follows:

a. immediate hoarseness, b. immediate ringing of the ears,

c. tightness in chest, shortness of breath and wheezing in 60 seconds,

d. generalized malaise, depression with a feeling of tightness in legs over the next hour, and

e. calf and bone tenderness, severe enough to prohibit the examiner from touching the legs lightly more than once, accompanied by obvious leg swelling, at the end of one hour after inhalation. Redness along the course of the saphenous vein. As shown in Table IV, pulse rates changed in all patients.
Table IV

Pulse Changes by Direct Challenge
Control
Cigarette Smoke
Petroleum Alcohol
Perfume Mixed
Foam Rubber
Pine-scented Floor Wash
Natural Gas
1
 75
95
100
80
85
120
150
2
 70
83
85
70
76
100
95
3
 65
78
80
110
65
70
70
4
 60
130
100
75
65
70
85
5
 73
75
75
80
80
85
80
6
 70
90
85
80
85
130
35
7
 67
50
75
75
67
85
69
8
 78
78
85
85
82
79
79
9
 79
90
85
90
84
79
85
10
 71
85
90
75
75
80
79

 

LABORATORY DATA

Eight out of 10 patients had WBC counts depressed below 6,000 while the remaining two were a few hundred above. All counts increased to the mid-normal range by the end of the fast and before testing began. IgG was elevated in one patient (1,600 mg/dl) and at the upper limits of normal in two others (1,200, 1,250 Fg/dl). The other immunoglobulins were unchanged, including IgE, which ranged between 25 to 50 mg/dl. Serum C3 remained normal in all but one patient and this was low, while serum C4's (Table V) were initially elevated in all patients and in five had returned to normal by the end of hospitalization. Alpha 1 and 2 macroglobulins were slightly depressed in two patients. All other laboratory tests were unchanged.

Table V

Serum ComplementCC4. Control (20-40)C10 Patients
 

Patient before E.C.
End of Fasting
End of Hospitalization
1
58
52
40
2
92
65
50
3
59
52
47
4
62
55
46
5
61
54
38
6
65
58
44
7
62
56
39
8
58
62
42
9
57
48
35
10
52
45
40

 

DISCUSSION

Patients with environmentally triggered phlebitis were found to exhibit many manifestations of what is generally accepted as atopic disease, although the overall syndrome probably is not atopy in the classic sense. This, of course, does not negate the observed fact that environmentally triggered phlebitis occurs and can be cleared and reproduced by the institution of rigid environmental control. Though phlebitis was easily reproduced by single incitants, the cumulative effect of multiple small reactions must account for the recurring phlebitis in these patients. This cumulative effect was emphasized during the ingested chemical testing in the four patients who took more than one chemical meal before their phlebitis flared. The cumulative effect phenomenon may well explain why the phlebitis was not reproduced in two of the patients in this series. They had been desensitized for at least 10 days and no reactions were allowed to accumulate during testing. The feeling of tightness in the legs, which they experienced, probably was a prodromal to phlebitis since it initially occurred in all patients in whom the phlebitis was reproduced. The testing was terminated because it was not beneficial to the patient to continue this particular incitant. Probably another dose of the particular incitant would have allowed the cumulative effect to bring on the phlebitis.

It was clear from observing these patients that the initial rapidity and subtlety of reactions both from ingestion and inhalation would be undetectable outside an environmental control unit and is probably why these triggering agents have not been defined before. At times the initial food reactions, though quite evident under environmental control, were mild and would crescendo over 24 to 48 hours. Out-of-hospital testing might have missed the initial reaction and called this a delayed reaction and probably led to unreconcilable confusion as to the triggering agent. It is interesting to note that all patients were able to appreciate the triggering agents once they were dismissed from the unit, thus being able to manipulate their home environments and diets to remain phlebitis-free. However, this sometimes meant radical changes in the home, including removal of all the gas elements (even their furnaces), foam rubber, odorous plastics, and rugs. The wide spectrum and multiplicity of foods as triggering agents of various symptoms in a given individual have not been generally found in the literature but are known to occur in some few patients. It is apparent from this series that the study of individual food susceptibilities under controlled hospital conditions should be re-examined since the subtlety and rapidity of their actions probably were not always previously appreciated under less controlled circumstances. Other forms of vascular diseases should also be studied in this light, since they may have susceptibilities to multiple environmental incitants.

It was rapidly evident early in the study that attention to where and how food was raised, transported, stored, and prepared was one of the keys to success in obtaining reproducible symptoms and signs. It was necessary to develop a network of human monitors who were susceptible enough to ingested chemicals to be certain the food was as pure as possible. This ensured that the ingested test reactions were to the foods and not the chemicals on or in them. Once this system was established, reproducibility of food reactions was 99%. Food acquisition was a problem at first since no grocery store food could be used, except when testing contaminated food, but persistence allowed the development of producers of chemically less contaminated food. This now has developed into a viable food cooperative acting as a supplier for both hospital testing and long-term outpatient treatment.

 Testing for the inhalant chemical triggering agents also initially presented many obstacles. When developing rooms which are chemically odor free, we found it was necessary not to allow any pesticide extermination or odorous cleaning agents to be used. This required intensive schooling of all the involved personnel, including the housekeepers. Attention to detail in construction materials is necessary since it was found for the last five years all plaster board usually used in modern construction has a potent synthetic in the outer paper that will outgas and produce symptoms or prohibit clearing in susceptible individuals. Hard plastics have very little outgassing and proved acceptable after a period of six months to one year of aging. The same could be said for water-based petroleum paint. It soon became obvious that to obtain a basal state in individuals susceptible to inhaled chemicals that rooms constructed of glazed stone, glass, and plaster were the most efficient. At present tests for inhaled chemicals are crude. However, when one realizes that with more than 10,000 synthetic chemicals in our environment no practical way is available to test each one individually. Certainly, as familiarity with environmental control units and techniques progresses better methods for testing chemical susceptibility will be developed. At least with the present method the reactions are consistently reproducible and allowed us to induce and clear the phlebitis as desired.

The intrinsic mechanism for occurrence of this type of phlebitis is unclear. However, the answer surely lies in the intricate interaction of the antigen-antibody, complement, kinin, and fibrinolytic systems. Our data does not incriminate the IgE aspects of the a-a-system since all were below 50, but then reactions could be occurring on the vessel wall without serum elevation. Since immune complex studies were not done in this series, the a-a-aspect is still open to question. The elevated C4's, in all patients, incriminate the complement system, either as part of a distorted immune response or the inflammatory result. Direct triggering of the clotting mechanism could have occurred locally without disturbance of the systemic clotting studies and thus would be compatible with our normal clotting studies. Direct triggering of the kinin system by foods and chemicals has been shown to occur in vitro (5.6) and could also have contributed to the triggering of the clotting mechanism. Unfortunately, we were not able to measure kinins in this study. Surely, the fact that the vascular tree has an inherent affinity to phenol 15 times greater than any other system in the body7 has a direct bearing on why inhaled and ingested chemicals triggered this type of phlebitis.

Regardless of the fact that the precise intrinsic mechanism for environmentally triggered phlebitis is not specifically defined, the entity clearly exists. It can be cleared without medications and reproduced by withdrawal and challenge under rigidly controlled conditions. It emphasizes to us the need to search for multiple triggering agents for a specific clinical entity.
 
 

ACKNOWLEDGMENT

The author thanks Dr. William C. Grater for his kind assistance in the preparation of the manuscript.
 
 

REFERENCES

1. Anderson, W.A.D. 1957. The blood and lymphatic vessels. Pathology, Ch. 20, 534. St. Louis: The C.V. Mosby Co.

2. Nicolaides, A.N. 1975. Thromboembolism: Etiology Advances in Prevention and Management. Baltimore: University Park Press.

 3. Randolph, T.E. 1965. The ecologic unit. Hospital Management [Part I] 97:45; [Part II] 97:46. 4. Randolph, T.E. 1962. The Ecologic History: Human Ecology and Susceptibility to the Chemical Environment, 10. Springfield, IL: Charles C. Thomas.

5. Rocha, E., and M. Silva. 1970. Kinin hormones with special reference to bradykinin and related kinins. Kinin Food Triggering Chemicals. Springfield, IL: Charles C. Thomas,

6. Miller, R.L., M.J. Reichgotti, and K.L. Melmon. 1973. Biochemical mechanism of generation of bradykinin by endotoxin. Inf Dis [Suppl 1] 128:144.

 7. Nour-Elden, F. 1970. Update of phenol by vascular and brain tissue. Microvascular Res 2:224.