Anosmia after Intranasal Zinc Gluconate Use

Anosmia after Intranasal Zinc
Gluconate Use
Bruce W. Jafek, M.D., Miriam R. Linschoten, Ph.D., and Bruce W. Murrow, M.D., Ph.D.
ABSTRACT
Background: Zinc is an essential mineral. Beneficial zinc
absorption takes place via enteral, parenteral, or cutaneous
routes. However, direct application to the olfactory epithelium
has been reported to cause loss of smell. Recently, intranasal
zinc gluconate has been recommended as a treatment for the
common cold. Severe posttreatment hyposmia and anosmia
have been observed.
Methods: The case report of a typical patient is presented and
analyzed in detail, followed by a series of patients with severe
hyposmia or anosmia after the use of intranasal zinc gluconate.
Results: Although interindividual variation in drug response
and drug effect is apparent, the severe hyposmia or anosmia
appears to be long lasting or permanent in some cases. The
mechanism of olfactory loss is thought to be the direct action
of the divalent zinc ion on the olfactory receptor cell.
Conclusions: Zinc ions are toxic to olfactory epithelium. Reports of severe hyposmia with parosmia or anosmia have
occurred after intranasal use of zinc gluconate. (American
Journal of Rhinology 18, 137–141, 2004)
Z
inc is an essential element found in almost every cell. It
is involved in a number of areas of human physiology, including the activity of ⬃100 enzymes,1 the immune
system,2,3 wound healing,4,5 the senses of taste and smell,4,5
and DNA synthesis.6 Zinc also supports normal growth and
development during pregnancy, childhood, and adolescence.7,8 The deleterious effects of both deficiency2,5,6,9–11
and toxicity (acute and chronic)2,12,13 are described.
From the Department of Otolaryngology—Head and Neck
Surgery, University of Colorado School of Medicine, Denver,
Colorado
Address correspondence and reprint requests to Bruce W.
Jafek, M.D., F.A.C.S., UCHSC (B-205) Otolaryngology, 4200
E. Ninth Ave., Denver, CO 80262
Copyright © 2004, OceanSide Publications, Inc., U.S.A.
Beneficial zinc absorption takes place via enteral, parenteral, or cutaneous routes.5,13 However, direct application to
the olfactory epithelium was known to be toxic over 60
years ago.14–16 This toxicity is thought to be caused by the
direct effects of the divalent zinc ion on the olfactory
receptor cell.17–19 Otherwise beneficial divalent ions (e.g.,
copper, cadmium, and barium) also have been shown to be
toxic when applied directly to the olfactory epithelium.17–19
Recently, intranasal zinc gluconate has been recommended
as a treatment for the common cold.20 We present a series of
patients with severe hyposmia or anosmia after the use of
intranasal zinc gluconate.
METHODS/OBSERVATIONS
Case Reports
55-year-old man with previously normal taste and
smell developed clear rhinorrhea and congestion and
treated himself with over-the-counter (OTC) zinc gluconate* for a self-diagnosed cold. He noted immediate
burning in his nose and did not use the spray again. He
noted immediate anosmia, which was persistent. He also
noted a “slightly salty” taste, which was intermittent. He did
not smoke. He had rheumatoid arthritis, for which he took
Remicade (Imfliximab, CENTOCOR, Inc., Malvern, PA)
and regular bursts of prednisone (which did not subsequently improve his anosmia). He also took Arava (Leflunomide, Aventis Pharmaceuticals, Inc., Kansas City, MO)
until 8 weeks before the incident and methotrexate (for the
arthritis) until 10 weeks before the incident. His other medications included Prilosec (Omeprazole, AstraZeneca PLC,
London, U.K.), Allegra, (Fexofenadine HCl, AstraZeneca
PLC), and Flonase (Fluticasone Propionate, Glaxo Welcome, Inc., Research Triangle Park, NC). He had some
indications of lupus and his liver function tests were “borderline normal.” He was otherwise in excellent health.
He was seen by an otolaryngologist, and the otolaryngo-
A
*Zicam, Mattrixx Initiatives, Phoenix, AZ
American Journal of Rhinology
137
logical examination was normal. A magnetic resonance
image, with and without contrast, was normal. No evidence
of sinus disease was seen.
Detailed chemosensory evaluation was done. Absolute
monorhinal butanol sensitivity was determined with a twoalternative forced-choice method using a maximum-likelihood adaptive staircase procedure.21 This procedure continuously estimates the sensory threshold while keeping track
of the pattern of responses, as well as response bias. The
threshold results indicated severely limited detection ability
bilaterally. Odor identification was absent on the right side
and severely limited on the left. The composite score indicated severe hyposmia. Using Vicks VapoRub (Proctor &
Gamble, Cincinnati, OH) as a trigeminal stimulant, bilateral
normal trigeminal activity was determined. Taste testing
was normal except for the salty taste, which was partially
extinguished by 0.5% Diclone (Antra, Astra Pharmaceutical
Products, Inc., Westborough, MA) application. The severe
hyposmia has persisted, unchanged, 10 months posttesting
and 23 months postincident.
Patient Series Data
ur taste and smell center (Department of Otolaryngology, University of Colorado School of Medicine,
Denver, CO) receives numerous inquiries from patients
with chemosensory dysfunction. By reviewing these, a
number of patients with loss of smell after the use of
intranasal zinc gluconate have been identified.
Seven men and three women, aged 31–55 years comprised the study series. The distinguishing characteristics
were immediate, severe burning of the nose (similar to that
reported previously in the zinc literature16) after the use of
intranasal zinc gluconate, followed by severe hyposmia
with parosmia or anosmia in patients who reported previously normal taste and smell and no other causative history
to account for the loss. Through the use of the Colorado
Chemosensory Questionnaire, the possibility of other
causes of chemosensory loss (e.g., previous sinus surgery or
chronic sinusitis, nasal polyposis, or other pathology or use
of potentially toxic medications) was ruled out. We assume
that additional patients did not contact us and that additional
cases still have not been diagnosed, raising the apparent
incidence of the smell loss.
O
DISCUSSION
n 1934, investigations of the local effect of chemicals in
controlling viral disease (polio) in experimental animals
had shown the apparent beneficial effects of intranasal alum
in preventing polio in exposed monkeys.14 Intranasal picric
acid then was tried with apparent greater success. Schultz
methodically began testing a long list of chemicals in the
hope of finding the ideal one that offered the most protection and could be used safely on humans.22 He found what
he thought was the “golden chemical,” zinc sulfate.22,23 The
theory was that zinc ions “coagulated natural proteins in the
olfactory epithelium, forming a protective coating around
I
138
the nerves, which prevented them from absorbing the polio
virus.”14 At that time, the hypothesis of the pathogenesis of
polio was that the virus was inhaled into the olfactory cleft
and then attacked the olfactory nerves to travel “along these
tiny nerves to the spinal cord where large motor bodies are
located.”14 Supporting this theory, the virus had been recovered from the nasal discharge of polio patients as well as
from monkeys artificially infected with the disease. Invariably, the olfactory mucosa showed the marks of the virus
and microscopic pathological changes were found along the
olfactory nerves extending to the motor nerve cells of the
spinal cord.14 When the olfactory nerves were cut, uptake of
the virus in exposed monkeys appeared to be blocked, while
the disease occurred in control animals (monkeys with
intact olfactory nerves). The watchword became, “protect
the nose and prevent polio.”24
Schultz initially tried the alum-picric acid on humans as
an intranasal spray during the summer of 1936 when an
epidemic of polio struck the southern states.14 The results of
the experiment in ⬎4600 children and adults treated were
“most discouraging,” but the failure was attributed to the
haphazard manner in which the solution was administered
and the study was termed “unscientific” and “confidence in
chemically induced prevention of the dread disease was
unabated.”14 Schultz argued that the Alabama experiment
had failed for two reasons: the alum-picric acid solution was
intrinsically inferior to his own zinc sulfate compound and
protection could only be gained by erecting an impenetrable
barrier around the olfactory nerves. The success of the
treatment would be judged by making the nerves “inactive
for a period of time,” the criterion for success being “loss of
the sense of smell.”14 “Protection against the virus” could
not be gained “unless the protective spray had temporarily
(authors’ emphasis) destroyed the sense of smell.”14 Several
authors debated the proper technique and cautioned that
only “trained experts” could properly administer the
zinc.24–26 To accomplish proper application, the zinc had to
be administered by experts in nose anatomy to reach the
critical area and had to be used often enough to produce the
desired anosmia, which Schultz reiterated was only a temporary condition.14
In 1937, therefore, during an epidemic in Toronto, Canada, special clinics manned by “nose and throat specialists”
sprayed a population of 5000 children twice at intervals of
10–12 days with a solution of 1% zinc sulfate and 0.5%
Pontocaine.15 There were additional “off protocol” administrations of the treatment as well, estimated as over “a
thousand more children,” as the public sought relief from
the dreaded disease. Most of the children suffered “some
discomfort” from the nasal spray. However, there were a
few cases of severe nasal pain that “continued for many
hours.”15 The most frequent complaints were headaches,
nausea or vomiting, and some stiffness of the neck. Sometimes the child developed transient fever, but overall, “reactions were singularly few.”14,15 “It was many months later
that Schultz began receiving complaints from physicians
May-June 2004, Vol. 18, No. 3
that many of their patients had suffered a complete and
permanent loss of the sense of smell.”14 Using relatively
primitive psychophysical testing, employing oil of cloves
and oil of spearmint, 10–13% of children were thought to be
anosmic, apparently permanently.14 Note that because oil of
cloves and oil of spearmint stimulate the trigeminal nerve, a
percentage of 10–13% is most likely a gross underestimation of the actual percentage of anosmics. Unfortunately, the
protective spraying with zinc sulfate did not alter the attack
rate of the disease and a more critical examination of the
olfactory tissues previously thought to be involved, along
with additional experimentation, ruled out the olfactory
epithelium as the sole portal of entry of the polio virus into
humans.15 But the toxic effect of zinc on human olfactory
epithelium was clearly shown. Although interindividual
variation in drug response and drug toxicity is apparent, the
effects appear to be dose related and long lasting or permanent in some cases. Subsequently, transient olfactory loss
has been reported in some of the studies of experimental
animals such as that of McBride.27 The use of intranasal
zinc was abandoned.
In 1976, Matulionis observed distinct patterns of degeneration and regeneration of the olfactory epithelium in mice
receiving intranasal irrigation with 1% aqueous zinc sulfate.28 During the first 24 hours after treatment, three progressive manifestations of the degenerative process were
seen: (1) a relatively mild condition which was characterized by surface irregularities produced by cell protrusions,
highly vacuolated cytoplasm, presence of large lysosomelike bodies, and prominent intercellular spaces; (2) a more
severe condition in which large areas of the epithelium were
detached from the basement membrane and cellular debris
was present in the nasal chamber; and (3) a condition of
total or near-total denudation of the epithelium of olfactory
mucosa. The basal lamina was continuous and intact in most
regions and the integrity of the subadjacent connective
tissue mostly was well preserved. The nerve bundles of the
fila olfactoria were noted to be in varying degrees of degeneration during the course of the experiment, with the
most advanced neural degeneration from 24–72 hours after
treatment.
In 1978, Harding, described immediate and total anosmia
in mice irrigated with intranasal 0.17 M ZnSO4.17 This
anosmia persisted for 6 weeks in at least 80% of the treated
animals and 4 months in one-half of the treated animals.
Changes were still apparent at 1 year, the limit of the
experimental observation.
By 1982, Cancalon attributed the “necrotic effect” of
various salt solutions to the divalent “zinc cation” in irrigation experiments on the catfish olfactory mucosa, using
concentrations of 6–960 mM of zinc sulfate.18 He noted that
ZnSO4 and ZnCl were “equally effective in destroying the
olfactory epithelium, offering proof that it was the zinc
cation that produces the toxic effects. He reported that the
damage was very reproducible, largely concentration independent, and almost completely specific for the olfactory
American Journal of Rhinology
receptor cells. The nonsensory respiratory cells were unaffected. The sustentacular cells surrounding the receptor cells
were affected mainly by a loss of microvilli. The olfactory
cells started to degenerate within a few hours and by day 4,
only 20% of the original receptor population remained.
Mucosal basal cell mitosis increased during days 3 and 4
and by day 7, the receptor population had reached 80% of its
original value. On the other hand, when the salt solution was
maintained in contact with the olfactory epithelium for
several days, only very limited regeneration occurred as
most of the lamellae were irreversibly destroyed.
In 1997, Mayer and Rosenblatt reported that the spray
application of ZnSO4 (1.74% in 0.9% saline) to the olfactory mucosa in rats produced severe nasal congestion that
cleared within 24 hours, followed by, in 48 hours, anosmia
in 80% of the treated animals.29
From a more basic standpoint, the transduction of odors
into electrical signals takes place on the surface of the
olfactory receptor cells and is necessary for olfactory function. In particular, an odorant binds to a cyclic nucleotidegated receptor that generates cyclic adenosine monophosphate, which in turn activates a nonspecific cation channel,
allowing Ca2⫹ entry into the cell. This Ca2⫹ then activates
a calcium-activated chloride channel that results in depolarization of the cell. The divalent cation Ba2⫹ is suggested to
block the nonspecific cyclic nucleotide-gated channel in
animals.30 This also appears to be the case in human olfactory receptor cells (Fig. 1). Zinc, a divalent cation, also may
block this channel and interfere with olfactory function.
Ongoing studies are evaluating both the short-term and
long-term effects of zinc on olfactory cell function.
In 2000, Hirt et al., recommended the intranasal use of an
OTC zinc gluconate nasal gel formulation* to bring the
medication closer to the causative organism, rhinovirus, in
alleviating the symptoms of the common cold, decreasing
the duration of symptoms by 75%.20 Citing the antirhinoviral activity of ionized zinc,31–33 they recommended that
the “mixed benefits” of zinc gluconate lozenges dissolved in
the mouth, affecting rhinovirus in the nose to prevent or
alleviate the symptoms of the common cold, could be improved by “delivery of ionic zinc directly to the site of
infection.”20,34,35 They noted that although 42% of “zinctreated patients” and 37% of controls described a “slight
tingling or burning sensation on intranasal zinc application,” five other potential side effects (nausea, bad taste
reactions, odor, dizziness, and drowsiness) were not found.
It is not apparent from their publication that they tested for
or considered olfactory deficits in their study group.
Other studies concluded that intranasal zinc was not
nearly as helpful in the treatment of the common cold.
Belongia found “no effect on the duration of the common
cold, but possibly mild and transient reduction in the severity of nasal symptoms, using 0.12% zinc sulfate nasal
*Zicam, Mattrixx Initiatives, Phoenix, AZ
139
Figure 1. Human olfactory epithelium was isolated from fresh
cadavers and EOG recording techniques used to study olfactory
transduction.40 (A) Cineole (100 ␮M) applied to the olfactory
epithelium produced a response (B) that in the presence of 5 mM
of Ba2⫹ was blocked. This effect was fully reversible after several
minutes of exposure to Ba2⫹. The bars below each trace indicate
the application time of cineole and note that there was a delay
before the start of the upward-going odorant response in panel A.
Saline control traces were subtracted from each trace and low
pass filtering was used.
spray.”36 Turner concluded that the commercially available
zinc gluconate gel* was “‘ineffective’ in preventing progression of an experimentally induced rhinovirus infection
33 mM of zinc gluconate in an emulsification of benzalkonium chloride, glycerine, hydroxymethylcellulose, sodium
chloride, and sodium peroxide, buffered to pH 7.2.”37
A single case report of anosmia due to inhalational zinc
soon followed.38
In 2003, Mossad concluded that ionic zinc (33 mmol/L of
zincum gluconium) “shortens the duration and reduces
symptom severity of the common cold in healthy adults.”39
140
Adverse effects were solicited by an open-ended telephone
question, the most commonly identified being “nasal stinging or burning.” Neither olfactory complaints nor evaluation
were mentioned.
Because patients use the intranasal zinc when they “feel
a cold coming on,” postviral anosmia should be considered
a cause for the chemosensory loss. Three factors argue
against this conclusion. First, the admittedly modest study
population had a male preponderance of more than 2:1, as
opposed to the 2:1 female ratio seen in postviral anosmia;
the patients in the intranasal zinc group also were younger,
on average, than reported postviral patients.40 Second, postviral anosmia typically occurs with “the worst upper-respiratory infection (URI) I’ve ever had.” Our study population
typically used the intranasal zinc early in the course of a
mild URI, and most convincing was the immediate, acute,
“burning” pain with the use of the zinc gluconate, followed
immediately by persistent severe hyposmia or anosmia.
Other explanations for the smell loss (e.g., post-traumatic,
etc.) were ruled out by a negative history in each case. A
Web site maintained by Dr. Karl L. Wuensch offers additional discussion of the issue of loss of smell after the use of
intranasal zinc.41
Recent advertisements have added a pediatric applicator
for intranasal zinc. This extension of the use of intranasal
zinc gluconate to the pediatric age group is of concern
because the use of intranasal zinc in this age group could be
expected to generate anosmia although this age group is less
likely to describe the symptom, resulting in repeated treatments rather than immediate discontinuation of the drug.
It should be noted that only a single trademarked preparation of zinc gluconate was available at the time of this
report and was used by each of the patients cited immediately before their loss of smell.* Subsequently, this brand
has been extended by the manufacturer to several products.
This communication only concerns the product containing
zinc gluconate.
CONCLUSION
n conclusion, the divalent zinc ion is reported to be toxic
to olfactory epithelium, the toxicity apparently being
related to both concentration and interindividual sensitivity,
but not the source of the ion (e.g., salt source, as shown by
Cancalon18 and others). The temporal association of the use
of intranasal zinc gluconate with the development of severe
partial or total loss of the sense of smell raises significant
concern regarding its safety for intranasal application in
humans. Given the prevalence of viral URIs, the strong
desire of patients for symptomatic relief and the widespread
availability and marketing of OTC products for this purpose, there is the potential for a very large number of people
to be exposed to intranasal zinc gluconate. Therefore, even
if the frequency of loss of smell is low, the number of
I
*Zicam, Mattrixx Initiatives, Phoenix, AZ
May-June 2004, Vol. 18, No. 3
people affected by this treatment could be alarmingly high.
The public may assume that because intranasal zinc gluconate is sold as an OTC “patented, homeopathic” preparation, containing a “natural,” or even “essential” element,
that it is safe. This report raises important questions about
that generalization. Because the effects appear to be somewhat dose-related, use of this drug in the pediatric age group
would be expected to generate an even larger incidence of
anosmia in this population and is especially concerning.
If history repeats itself, and the unexpected always happens, how incapable must man be of learning from experience.
—George Bernard Shaw (1856–1950),
Irish dramatist
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