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Immunodeficiency and other

clinical immunology

A combined respiratory and cutaneous

hypersensitivity syndrome induced by work
exposure to quaternary amines
Jonathan A. Bernstein, MD, Thomas Stauder, MD, David I. Bernstein, MD,
and . Leonard Bernstein, MD Cincinnati, Ohio

The quaternary amine, benzalkonium chloride, has been associated with cutaneous and
mucosal delayed hypersensitivity reactions and with paradoxicalbronchoconstriction after use of
aerosolized asthma medications. Until now, quaternaryamines have not been reported to cause
occupational asthma. We describe a case of occupational asthma caused by prolonged
exposure to a cleaning solution containing benzalkonium chloride in the workplace.
Single-blind, placebo-controlled, open-room challenges were performed to determine the specific
agent responsiblefor the patient's symptoms. Pulmonary function and epicutaneous challenge
tests were also performed. The patient had positive responses to challenges with a liquid toilet
bowl cleaner containing benzalkonium chloride but was unreactive to other agents tested.
Removal from the workplace resulted in complete resolution of symptoms. The exact
mechanisms responsiblefor occupational asthma induced by quaternary amines remain
unknown; however, this case emphasizes the importance of recognizing reactive chemicals as
possible causes. (JALLERGY CLIN IMMUNOL 1994;94:257-9.)
Key words: Quaternary amines, occupational asthma, benz.olkonium chloride

Over 40 different primary, secondary, and ter-

tiary amine compounds have been found to in- Abbreviations used
duce occupational asthma (OA).- 3 Quaternary BAC: Benzalkonium chloride
ammonium compounds have been widely used as FEV,: Forced expiratory volume in 1 second
preservatives in contact lens cleaning solutions, OA: Occupational asthma
aerosolized asthma medications, and household
products such as soaps, skin ointments, disinfec-
tants, and sanitizers. ' 3 Numerous cases of cuta- temic hypersensitivity reaction occurring after
neous and mucosal delayed hypersensitivity reac- prolonged exposure to a cleaning solution con-
tions to agents containing the quaternary amine, taining BAC in the workplace.
benzalkonium chloride (BAC), have been re-
ported. 3 BAC has also been associated with
A 22-year-old woman working in a factory that
paradoxical bronchoconstriction in patients with manufactured household cleaning products was first
asthma using aerosolized ipratropium bromide seen with acute onset of fever, shortness of breath,
and beclomethasone dipropionate. 4 5 However, chest tightness, nonproductive cough, and arthralgias,
these compounds have never been reported to which began 7 months after initiating employment.
cause OA. We now describe a case of BAC- Physical examination revealed mild cervical lymphade-
induced OA, which was preceded by a multisys- nopathy, conjunctivitis, tachypnea, bibasilar rales, bilat-
eral knee effusions, and erythematous papulovescular
skin lesions. Results of routine laboratory tests and
From the University of Cincinnati Medical Center, Division of sedimentation rate, complement levels, autoantibody
Immunology, Department of Internal Medicine.
screen, rheumatoid factor, and cryoglobulins were nor-
Received for publication Apr. 6, 1993; accepted Sept. 17, 1993.
Reprint requests: Jonathan Bernstein, MD, University of Cin- mal. Results of bacterial, fungal, and viral cultures for
cinnati Medical Center, 231 Bethesda Ave., ML 563, Cin- blood, skin, sputum, and synovial fluid were negative.
cinnati, OH 45267-0563. Serial chest roentgenograms during her hospitalization
Copyright © 1994 by Mosby-Year Book, Inc. revealed bibasilar pulmonary infiltrates. Pulmonary
0091-6749/94 $3.00 + 0 1/1/52646 function tests and measurements of lung volumes and
258 Bernstein et al. J ALLERGY CLIN IMMUNOL


I __ z-~_~ 20% Jall In FEVI
The immunopathogenesis of amine-induced
OA is currently unknown. It has been speculated
that these low molecular weight amines act as
haptens, which conjugate to endogenous proteins
such as human albumin, producing new antigenic
2.6 determinants capable of inducing immune re-
RRh ~rM L 1·I-
sponses.4 5 Quaternary amines have not been
0 10 20 45 60 90 120 18 previously reported to cause OA. This case docu-
Time from onset of challenge (minutes) ments a systemic hypersensitivity reaction occur-

[ IX'- clI..ay
#1 - - O f i.n FEI
Uoed Contr.l
Cn.,r #2 ring in a worker after prolonged exposure to a
mixture of quaternary amines containing N-alkyl
dimethylbenzyl and N-alkyl dimethylethylbenzyl
FIG. 1. Single-blind, controlled, open-room challenge ammonium chloride. On reexposure to the qua-
with the cleaning solutions.
ternary amine-containing solution at work, she
had respiratory symptoms consistent with OA.
diffusion capacity were not performed at this time. Skin The agent responsible for inducing her symptoms
and transbronchial biopsy specimens demonstrated was confirmed by means of open-room challenges.
nonspecific inflammatory infiltrates without vasculitic Only the liquid toilet bowl cleaner resulted in
changes. Empiric treatment with intravenously admin- a 38% decrease in FEV, 10 minutes after ex-
istered antibiotics and corticosteroids resulted in com- posure, with a maximum drop of 50% after 45
plete resolution of skin, joint, and pulmonary symp- minutes. Epicutaneous challenges with the indi-
toms. After returning to work, she experienced recur- vidual constituents of the liquid toilet bowl
rent wheezing and shortness of breath, which began cleaner demonstrated immediate cutaneous re-
shortly after reexposure to the cleaning products. At activity to a mixture of quaternary amines. Re-
this time she was referred to our center for further moval from her work environment resulted in
evaluation. Single-blind, placebo-controlled, open-
gradual improvement of her asthma. Interestingly,
room challenges were performed for each cleaning
product on separate days to determine the specific bronchial hyperreactivity in response to the toilet
agent responsible for her symptoms. Within 5 minutes bowl cleaner was demonstrated on rechallenge 2
after exposure to a liquid toilet bowl cleaner containing years later.
BAC, the patient experienced a diffuse erythematous, The clinical nature of this systemic reaction to
pruritic, urticarial rash on her face, neck, and chest; she BAC suggests that several immune responses
also experienced chest tightness and dyspnea. Pulmo- could be involved. The immediate drop in FEV
nary function testing revealed a 38% decrease in her and cutaneous reaction to BAC suggests the pos-
forced expiratory volume in 1 second (FEV1 ) after 10 sibility of an immediate hypersensitivity immune
minutes with a maximum drop of 50% after 45 minutes, reaction. Specific IgE antibodies to a BAC-hu-
which slowly improved to baseline over 3 hours (Fig. 1). man serum albumin conjugate, however, could not
The subject was unwilling to cooperate with monitering
be demonstrated by ELISA (results not shown).
for a late-phase airway response. Her FEV, remained
unchanged in response to placebo, a drain declogging Her symptoms of fever and arthralgia/arthritis
solution, a window cleaner, and an air freshener. Epi- coupled with a cutaneous rash suggested a serum
cutaneous challenge tests were also performed with the sickness reaction, but markers of immune com-
individual components of the liquid cleaner. Within 15 plex disease were not demonstrated. A cell-
minutes after exposure to a 1:1 mixture of N-alkyl mediated immune response similar to hypersensi-
dimethylbenzyl and N-alkyl dimethylethylbenzyl ammo- tivity pneumonitis is supported by the bilateral
nium chloride, the worker had a 15 cm erythematous infiltrates on chest roentgenogram and lympho-
pruritic urticarial reaction, which persisted for several cytic infiltration observed in skin and bronchial
days. She was unreactive to the other agents and biopsy specimens.
chemical constituents tested. A control subject had In conclusion, we have presented evidence to
negative responses to the pulmonary and epicutaneous
support a diagnosis of OA induced by a toilet
challenges. Subsequent removal from the work environ-
ment resulted in complete resolution of her symptoms. bowl cleaner containing the quaternary amine,
A follow-up open-room challenge study with the liquid BAC. The precise mechanisms responsible for
toilet bowl cleaner 2 years later resulted in a similar induction of bronchial sensitivity to quaternary
skin rash with a decrease in FEV, after 10 minutes of amines remain unknown. However, this case em-
exposure. phasizes the importance of recognizing reactive

chemicals as causes of bronchial reactions in the 3. Bernstein IL. Allergic reactions: other addition products.
workplace. In: Weiner M and Bernstein IL eds. Adverse Reactions to
Drug Formulation agents. New York: Marcell Dekker Inc,
4. Zhang YG, Wright WJ, Tam WK, Nguyen-Dang TH,
1. Hagmar L, Bellander T, Eng M, Bergoo B, Simonsson BG. Salome CM, Woolcock AJ. Effect of inhaled preservatives
Piperazine-induced occupational asthma. J Occup Med on asthmatic subjects. II. Benzalkonium chloride. Am Rev
1982;24:193-7. Respir Dis 1990;141:1405-8.
2. Malo JL, Bernstein IL. Other chemical substances causing 5. Sly RM. Effect of inhaled preservatives on asthmatic
occupational asthma. In: Bernstein IL, Malo JL, Yeung subjects: II. Benzalkonium chloride. Am Rev Respir Dis
MC, Bernstein DI, eds. Asthma in the workplace. New 1990;142:1466-7.
York: Marcell Dekker Inc, 1993:481-502.

Fatal pulmonary nocardiosis in a patient with

chronic mucocutaneous candidiasis
Joram S. Seggev, MD Las Vegas, Nev.

Chronic mucocutaneous candidiasis (CMC)

consists of infection of the skin, nails, oral cavity, Abbreviations used
and esophagus, most commonly with Candida ALP: Alkaline phosphatase
albicans, and is associated with various immuno- CMC: Chronic mucocutaneous candidiasis
IL-2: Interleukin 2
logic defects. ' 2 Severe non-candidal infections, as
a major complication of CMC, have not been well
documented until recently. 2' 3 The present case is hood and adolescence, he experienced recurrent upper
a report of a patient with unusual features, who respiratory tract infections and pneumonia.
eventually succumbed to overwhelming Nocardia Physical examination at the time of admission was
infection 10 months after an apparent cure. remarkable for cachexia, hypopigmented areas on the
hands and arms, clubbing, dystrophic nail changes, and
CASE REPORT white patches on the tongue and throughout the oral
A 20-year-old man, diagnosed with CMC at 22 cavity and pharynx. The chest was clear. Pertinent labo-
months of age, was admitted to the University of ratory data included microcytic, hypochromic anemia,
Missouri-Columbia Health Sciences Center for treat- elevated alkaline phosphatase (ALP) and alkaline phos-
ment of Nocardia pneumonia. At the age of 5 years, he phatase y-glutamyl transferase levels, normal parathy-
was reported to be euthyroid and to have partially roid hormone and cortisol levels, and a negative ELISA
responded to administration of transfer factor.4 Hy- result for human immunodeficiency virus. An esophago-
pothyroidism was diagnosed at age 12, requiring daily gram was interpreted as showing evidence of candidal
administration of thyroxine. One year later, administra- esophagitis, and a chest roentgenogram revealed a non-
tion of ketoconazole was started. Throughout child- homogeneous infiltrate in the left lower lobe. Treatment
was started with sulfadiazine 3 gm/day, which led to
elevation of ALP to greater than 3000 U/ml; thus, min-
From the Allergy and Clinical Immunology Section, Depart- ocycline was substituted. One month later, increasing
ment of Internal Medicine, University of Nevada School of candidal lesions and bilateral maxillary sinusitis required
Medicine, Las Vegas. inpatient therapy with amphotericin B and cefazolin.
Received for publication Jun. 24, 1993; accepted Sept. 23, After discharge, minocycline and alternate-day keto-
1993. conazole administration (daily administration led to in-
Reprint requests: Joram S. Seggev, MD, Chief, Allergy/Clinical creases in ALP) were continued. Because the patient's
Immunology Section, Department of Internal Medicine,
University of Nevada School of Medicine, 2040 West sinusitis was uncontrolled, a Caldwell-Luc operation was
Charleston Blvd., Suite 503, Las Vegas, NV 89102. required. Minocycline was discontinued after 1 year,
J ALLERGY CUN IMMUNOL 1994;94:259-62. when chest roentgenograms were normal. Ketoconazole
Copyright © 1994 by Mosby-Year Book, Inc. eventually became ineffective in controlling his candidi-
0091-6749/94 $3.00 + 0 1/1/52649 asis, and treatment was changed to alternate-day admin-