Michael M. Miller

Trimellitic anhydride-induced airway syndromes: Clinical and immunologic studies☆

This report describes a spectrum of respiratory symptoms in workers exposed to trimellitic anhydride (TMA), a biologically reactive chemical used in the plastics industry. Fourteen workers who had worked on a unit which synthesized TMA were evaluated by clinical and immunologic methods. Respiratory syndromes induced by TMA inhalation included asthma and rhinitis of the immediate type, late onset asthma with systemic symptoms, and airway irritation. TMA was shown to couple rapidly to human serum albumin, forming an immunoreactive hapten-protein complex. The workers immunologic reactivity to this complex could be quantitated and correlated with the three respiratory syndromes. The asthma-rhinitis syndrome was mediated by IgE antibody specific for the TMA hapten. The syndrome of late onset asthma with systemic symptomes was accompanied by elevated levels of TMA-specific IgG antibody. Rheumatoid factor in high titer was found in one worker with IgE-mediated asthma and in two workers with asthma of late onset. Lymphocyte reactivity of TMA-HSA was demonstrated in three workers representative of the three clinical syndromes. Leukocyte histamine release was demonstrated to TMA-HSA in one worker with high levels of IgE antibody specific for TMA-HSA who had severe symptoms of acute rhinitis and asthma.

Chronic hypersensitivity lung disease with recurrent episodes of hypersensitivity pneumonitis due to a contaminated central humidifier

A child with a 4‐year history of acute and chronic respiratory symptoms of unknown aetiology was investigated for hypersensitivity pneumonitis. Lung disease due to inhalation of material from a contaminated central humidifier was suggested by the clinical history, the presence of precipitating antibodies in the serum against the humidifier water, a pulmonary response to challenge with the humidifier water, and marked improvement after removal of the humidifier. No fungi were cultured from the humidifier nor were antibodies against a number of fungal antigens identified by radioimmunoassay inhibition techniques. Antigenic material was found in the humidifier water and the household water prior to its reaching the humidifier. This antigenic material was not found in laboratory tap water supplied from the same general source (Lake Michigan) but from a different pumping station. Three of the childs siblings gave histories suggestive of a single concurrent episode of acute hypersensitivity pneumonitis and one sibling had a history suggestive of chronic hypersensitivity lung disease. No association could be found between HLA‐haplotypy and disease in the patient and the siblings.

Methacholine and physostigmine airway reactivity in asthmatic and nonasthmatic subjects

Inhalation challenges using methacholine and physostigmine were performed in 3 human asthmatic and 3 nonallergic normal subjects. Plethysmographic measurements of specific airways conductance (Gaw/Vtg) were used to monitor the response. The dose required to produce a 17% fall in Gaw/Vtg was significantly lower in asthmatic subjects than in normal subjects for both physostigmine (p less than 0.0125) and methacholine (p less than 0.05). Moreover, in all subjects the relative airway sensitivity to methacholine correlated with the relative airway sensitivity to physostigmine. Both methacholine and physostigmine are cholinergic agents. Whereas methacholine acts directly at the end organ cholinergic receptor, physostigmine acts by increasing release and decreasing destruction of endogenous acetycholine at the vagal distal innervation. This suggests that the cholinergic airway hyperreactivity characteristic of asthma is a manifestation of end organ hypersensitivity.

Differential Airway Reactivity to Carbachol and Physostigmine Sulfate in Rhesus Monkeys with and without Reagin-Mediated Respiratory Responses

Bronchial airway reactivity to carbachol (CAR) and physostigmine (PHY) was individually measured in three rhesus monkeys with and three rhesus monkeys without reagin-mediated respiratory responses (RR). The three monkeys with reagin-mediated RR demonstrated bronchial hyperreactivity to CAR (p less than 0.25) but not PHY when compared with the three control monkeys. No correlation between airway reactivity to CAR and PHY was noted in all six monkeys. We conclude that monkeys with reagin-mediated RR possess airway hyperreactivity to the exogenously administered acetylcholine analogue CAR, but not to the endogenous acetylcholine which is released in vivo by PHY.

A statement on the question of allergy to fluoride as used in the fluoridation of community water supplies

A request to the American Academy of Allergy has been made by the United States Public Health Service for an evaluation of the question of allergy to fluoride as used in the fluoridation of community water supplies. I t was further requested that such an evaluation include a review of clinical reports of allergy to fluoride and express an opinion whether or not such reports constitute valid evidence of a hypersensitivity reaction. The response to this request has been handled as follows: Reports of allergic reactions have been reviewed. First, these reports were evaluated in an attempt to determine whether or not there is sufficient clinical or scientific information to classify any case of presumed fluoride allergy in one of the four major classes of hypersensitivity reaction (types I to IV).^ These immunologically mediated reactions are the anaphylactic or reaginic, the cytotoxic, the toxic complex, and the delayed-type reactivity.^ Second, the reports were evaluated to determine whether or not there was sufficient clinical evidence to support the possibility that intolerance or allergy to fluorides might occur as one of the less-well understood types of drug reactions that may or may not be immunologically mediated.^ The reports of fluoride allergy reviewed^ listed a wide variety of symptoms including vomiting, abdominal pain, headaches, scotomata, personality change, muscular weakness, painful numbness in extremities, joint pain, migraine headaches, dryness in the mouth, oral ulcers, convulsions, mental deterioration, colitis, pelvic hemorrhages, urticaria, nasal congestion, skin rashes, epigastric distress, and hematemesis. The review of the reported allergic reactions showed no evidence that immunologically mediated reactions of the types I to IV had been presented. Secondly, the review of the cases reported demonstrated that there was insufficent clinical and laboratory evidence to state that true syndromes of fluoride allergy or intolerance exist. As a result of this review, the members of the Executive Committee of the