Experiences with Piromen in the Treatment of Allergic Disorders

The recognition and treatment of allergy in the past thirty years has shown marked progress. More and more conditions of previously unknown etiology are now being classified as allergic in origin.

A few of the milestones on the road to a better understanding of the allergic state may bear repeating: (1) the development of potent extracts for testing and treatment, (2) the reproduction of symptoms in cases of possible food allergy by test feeding after elimination of the suspected food from the diet for a few days, rather than reliance on skin tests, (3) the use of elimination diets in the diagnosis of food allergy, (4) the pulse-diet technique of Coca, (5) the stress concept of Hans Selye, (6) the recognition of psychosomatic factors, (7) the development of adrenocorticotropic hormone (ACTH) and the corticosteroids, (8) the discovery of the antihistaminics, (9) and finally the awakening interest in nutritional adequacy as a prerequisite for normal body chemistry.

In spite of these advances every physician encounters refractory cases that respond unsatisfactorily to every therapeutic effort. A nontoxic, nonspecific substance capable of mobilizing body defenses against allergic attack has long been sought. Piromen® showed promise in this respect and its clinical application forms the basis of this preliminary report.

Pharmacology and Other Properties

Piromen is a sterile, colloidal solution containing a complex polysaccharide obtained from a relatively nonpathogenic strain of Pseudomonas aeruginosa. Intensive studies from pharmacologic and clinical. aspects have shown it to be relatively nontoxic and nonanaphylactogenic.^7,8

Some investigators have found evidence in both animals and humans that injections of Piromen produce a leukopenia followed in a few hours by a neutrophilic leukocytosis. This suggests stimulation of the pituitary adrenal axis.

The leukocytic response to ACTH in dogs disappears following adrenalectomy, whereas that to pyrogens remains.¹² In cats, however, bilateral adrenalectomy abolishes the characteristic leukocytic response to both these compounds. The variable results may be due to technical difficulties or a species difference.⁶

Windle, et al, working with rabbits, have found evidence of adrenal cortical hypertrophy together with hyperactivity of the bone marrow, lymph glands and spleen following repeated doses of Piromen.^13,14 In other words, activation of the reticuloendothelial system.

The action of Piromen on connective tissue suggests the inhibition of fibroblastic proliferation and the enhancement of vascularization. Thus glial scar tissue is reduced and the growth of neurons through transected, feline spinal cords facilitated.^1,11,15,16

The work of Green⁸ is of dramatic interest. In a study of severely burned rats, this observer found that a single optimal dose of Piromen given within six hours after a burn, was as effective as multiple doses and resulted in an 87 per cent survival rate as compared to 100 per cent mortality in the control group. Sub-lethal burns healed more rapidly and with better epithelization than the controls. Experimental evidence thus supports the concept of an endocrine, reticuloendothelial and peripheral action.

Encouraging clinical reports in the treatment of perennial allergic conditions, poliomyelitis, neurodermatitis and depressed emotional states have recently appeared in the literature.^{2,4,5,9,10,17,18}

Methods

The present contribution is entirely clinical and without controls, except that most cases were of a chronic nature and had responded poorly to previous treatment. Piromen was used alone in thirty-nine cases and added to prior therapy in thirty-one. Nutritional support as indicated was basic in all.

Under these circumstances such potent therapeutic agents as ACTH and Cortisone would have produced a high percentage of at least temporary response. Such was not the case in this series and yet some very interesting results were observed.

Seventy patients were treated for a long enough period to be included in this report. Duration of treatment varied from three days to twenty two months. With the exception of poison oak dermatitis, the minimum period was three weeks. Improvement, if it were going to occur, almost always appeared before the sixth injection.

Ages ranged from a tender two years to a mellow seventy-two. Of eighteen patients under the age of fifteen years, the number responding favorably to Piromen was fifty per cent greater than the average for the whole group. This is not surprising, for youth is resilient.

Two-thirds of the patients were females and one-third males. Allergic conditions treated included the following: asthma 24, dermatitis venenata 10, allergic rhinitis 9, neurodermatitis 6, hay fever 4, chronic urticaria 2 and miscellaneous conditions such as penicillin reaction, Runner’s ulcer, herpes labialis, neuritis, acute bursitis, and migraine 15.

Piromen injections were given intravenously in half of the cases and intramuscularly or subcutaneously in the remainder. Treatment was usually initiated with 1 gamma and increased by 1 gamma every two or three days until improvement or constitutional reaction occurred. The dose was then stabilized or reduced 25 to 40 per cent in the case of reactions and held at that level. Relief of symptoms was an indication for repeating the same dose at intervals of one to three weeks. as necessary to maintain remission.

Considerable individual variation intolerance was soon apparent. The average dose by both routes of administration was between 0.5 and 10 gamma, with most cases receiving 5 gamma or less. The smaller doses may be more desirable and the subcutaneous route preferable.

While some cases were treated no oftener than once weekly, dermatitis venenata due to poison oak seemed to warrant daily injections.

One patient tolerated 50 gamma intravenously without reaction or improvement. An asthmatic child of eight, under treatment with ACTH for intractable asthma, was given large intravenous doses in hopes of producing a remission. In spite of 30 gamma, followed by 60 gamma two hours later, a temperature of only 100.6 was achieved. The antipyretic effect of ACTH has been noted before. No benefit was obtained. In contrast, symptoms have been provoked by as little as 0.5 gamma intravenously and subcutaneously. Children and elderly people must be treated cautiously.

Constitutional reactions consisted of malaise, generalized aching, chilly sensations (one tooth-chattering chill), headache and fatigue lasting from one to twelve hours. No sequelae were observed. Following intravenous therapy the reactions occurred within two hours, but were delayed as a result of the subcutaneous route. A few asthmatics developed increased wheezing, but no anaphylactoid reactions were noted. Others, however, have reported fairly severe asthmatic flareups. This again suggests the subcutaneous route as being more desirable.

In a few cases repeated subthreshold doses eventually resulted in a reaction requiring reduction in future doses. In others, increasing tolerance necessitated a gradual increase in dosage to maintain improvement. A few relapses following original improvement may be based on the development of a refractory state. There was no apparent correlation between the elicitation of a reaction and the results obtained.

Results

Slightly more than half the cases obtained definite amelioration of symptoms. In about one fifth of the total, relief was very satisfactory. Seven individuals with severe, wide-spread skin lesions due to poison oak were comfortable after two or three daily injections of 5 to 10 gamma and the lesions had begun to regress. If these cases are removed from this series, only one half of the remainder could be considered improved, but of this thirty-five, fourteen were in the category of markedly improved. The poison oak group was classified as moderately helped. Perhaps this is too conservative.

Case Reports

Case 1.–V. S., a seventy-one-year-old male, complained of progressive wheezing, dyspnea and weakness of twelve years’ duration. He was getting some relief from aminophylline by mouth and Adrenalin by inhalation. Skin tests were negative. History included a twenty-five-year exposure to dust in a gold and silver mine. Roentgenograms showed pneumoconiosis.with marked fibrosis. There was no eosinophilia. Improvement was continuous after three weekly intramuscular injections which were thereafter given twice weekly. Maintenance dose is 8 gamma once a week There has been a marked gain in strength and eight pounds in weight. Wheezing is much improved and medication is needed only occasionally.

Case 2.–H. Q., a young man of fifteen, has had severe allergic rhinitis and asthma for twelve years. The onset followed pneumonia. Skin tests were positive to spring, summer and fall pollens and to house dust. Milk was an offender. Elimination diets and hyposensitization were ineffective. He has received 1 to 2 gamma of Piromen intravenously twice weekly for five months with repeated mild constitutional reactions. Although asthmatic attacks seem less frequent and less severe, there has been no significant improvement.

Case 3.–S. R., a girl of seventeen with a history of hay fever, recurrent urticaria and asthma for eleven years, has received intravenous Piromen in doses of 5 to 10 gamma once weekly for seven months. Sensitivities include house dust, tree and weed pollens. Improvement was noted after the second injection and has continued to date. Symptoms are now very mild and medication seldom needed. She has been carried through her pollen seasons without flareups.

Case 4.–Mrs. R. D., a housewife, aged sixty-one, gave a long history of asthma, paroxysmal tachycardia, hypertension, colitis and fatigue. By means of Coca’s pulse technique, numerous foods and house dust were found responsible and improvement was marked. Fatigue and mild symptoms remained as a result of encountering minor food and inhalant allergens. A gratifying sense of well being appeared after the first hypodermic of 1 gamma of Piromen, which was substituted for house dust she was receiving in the same manner. Injections were given twice weekly at first with a top dose of 1.5 gamma. She now “feels like a new woman” and can tolerate minor food allergens without symptoms. Major food offenders must be avoided, however. A three week interval was too long and the injections are now given once every two weeks.

Case 5.–E. McL., a man of fifty-six, had suffered from recurrent nasal polypi, profuse, thick nasal discharge and severe asthma for four years. No etiologic factors could be incriminated. Onset followed pneumonia. Antibiotics were of no help in preventing repeated status asthmaticus. Eosinophils in the peripheral blood averaged 20 per cent. Stools were negative for parasites. While taking cortisone, with excellent control of asthma and nasal complaints, he was given 4 gamma of Piromen intravenously three times weekly for a period of three weeks. During this time cortisone was gradually withdrawn, but his asthma returned in full force. When last heard of five months later he was living in another city and still taking cortisone.

Discussion

It was interesting to note that in those cases showing improvement there was no obvious change in circulating eosinophiles.

With the exception of the poison oak cases, all of which responded, improvement in other categories was about fifty per cent. If the major allergic complaint was relieved) other manifestations improved concomitantly.

A small series of cases such as this is not suitable for statistical analysis. Clinical evaluation is difficult because of many extraneous factors that do not lend themselves to control. Emotional and other forms of stress may vitiate the effects of therapy that might otherwise prove successful. Conversely, relief of tension may induce improvement and the result be attributed to whatever medication is being used at the time.

It is possible that relapses observed in a few patients responding favorably at first may be controlled by shifting to a pyrogen of different origin. It is also possible that a better understanding of optimum closage may improve results.

Obviously, Piromen is not the long-sought panacea for the treatment of allergic disorders. It should not therefore be relied upon as a routine form of therapy for these conditions. However, the impressive response of a small number of patients suggests that it will find a place in the treatment of selected cases, particularly when major allergens have been sought for, discovered and controlled insofar as that is possible.

The results obtained in the treatment of dermatitis venenata due to poison oak are particularly encouraging. Further evaluation is needed.

Summary

Seventy cases with a variety of refractory allergic disorders were treated with injections of Piromen (a standardized extract of Pseudomonas aeruginosa containing a complex polysaccharide). A scant majority responded with significant improvement. Seven cases of poison oak dermatitis showed a uniformly good response. Piromen is not recommended as a substitute for routine allergic management, but is of value in selected cases.

Addendum

Since this paper was written, twenty-six additional cases of poison oak dermatitis have been treated with Piromen, utilizing a daily hypodermic dose of 2 gamma. Most of these individuals had received prior therapy and the disorder had been present for one or more weeks without improvement. Two of these required ACTH on the fourth day of treatment because of poor response; the remainder were comfortable by this time. From two to eight injections were needed for clinical cure. Most patients responded to three or four.

 

References Cited:

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2. Fitch, Edna M. and Washburne, A. C.: “The effects of pyromen administered intravenously in sub pyrexial doses to depressed patients; A preliminary study.” New Eng. J. of Med., 245:961-966 (Dec.) 1951.
3. Greene, L. C.: “Healing of thermal burns in cats treated with pyromen.” Am. J. Physiol., 167 (Dec.) 1951.
4. Guerrieri, J. A: “Treatment of neurodermatitis with pyromen–A new therapeutic agent.” Clin. Med., 59:29-35 (Jan.) 1952.
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