Excercise-Intuced Anaphylaxis (EIA)

Background
Exercise-induced anaphylaxis (EIA) is a syndrome in which patients experience the symptoms of anaphylaxis, which occur only after increased physical activity. The symptoms include pruritus and urticaria (typically with giant hives), and, without emergency intervention, the patient may develop hypotension and collapse. Now increasingly recognized as more children and teenagers participate in physical activities and sports, exercise-induced anaphylaxis may become more common in the future. Those affected by the syndrome are typically accomplished athletes and have a history of atopy, but anyone can be affected.
The types of physical activities that have triggered episodes of exercise-induced anaphylaxis have included walking, dancing, racquet sports, swimming, jogging, bicycling, skiing, basketball, and sprinting. Hot humid weather and cold weather can precipitate episodes in some patients. If a patient has recurrent exercise-induced anaphylaxis, the episodes tend to be worse in the summer months. The first reported case of exercise-induced anaphylaxis was in 1979 by Maulitz and coworkers and was food-related, occurring in a 31-year-old patient who had ingested shellfish prior to long-distance running.1 Since then, many different allergens have been reported in the literature to have caused exercise-induced anaphylaxis, including shrimp, oyster, celery, cheese sandwiches, pizza, wheat gliadin,2 eggs, peaches, grapes, pomegranites,3 chick peas,4 pears, poppy seeds, soybean,5 and snails (which have been reported to have cross-reactivity with dust mites).
In 1980, Sheffer and Austen provided the first report of patients with exercise-induced anaphylaxis.6 Sixteen patients, aged 12-54 years, experienced exercise-induced anaphylaxis without a specific allergen exposure. Ten of these patients had onset of exercise-induced anaphylaxis in their teenage years, indicating that those who care for pediatric patients should be aware of this syndrome.
Exercise-induced anaphylaxis has been categorized in a few different ways in the literature. Classic exercise-induced anaphylaxis is the most common type. Sheffer and Austen (1980) originally described 4 phases in the sequence of symptomatology of classic exercise-induced anaphylaxis.6 A prodromal phase is characterized by fatigue, warmth, pruritus, and cutaneous erythema. The early phase follows, with the urticarial eruption that progresses from giant hives (about 10-15 mm in diameter) to become confluent and may include angioedema of the face, palms, and soles. Then, the fully established phase occurs, which can include hypotension, syncope, loss of consciousness, choking, stridor, nausea, and vomiting and can last 30 minutes to 4 hours. The final phase is the late or postexertional phase, which is characterized by prolonged urticaria and headache persisting for 24-74 hours.
Another type of exercise-induced anaphylaxis is variant-type exercise-induced anaphylaxis, which is similar to classic exercise-induced anaphylaxis, except the typical giant hives are not observed. In their place are small punctate skin lesions, more typical of cholinergic urticaria, but the syndrome does lead to hypotension and collapse if allowed to progress. The variant type of exercise-induced anaphylaxis accounts for approximately 10% of cases.
Familial exercise-induced anaphylaxis has been described involving patients with a family history of exercise-induced anaphylaxis and atopy. No inheritance pattern has been established.
Two forms of food-dependent exercise-induced anaphylaxis have been described. Inherent in the definition of food-dependent exercise-induced anaphylaxis is that the food or exercise alone does not produce symptoms. First, specific-food exercise-induced anaphylaxis in which a specific food is known to be the offending allergen is recognized. Second, nonspecific-food exercise-induced anaphylaxis in which no specific food is known, but eating any food prior to exercise causes symptoms of exercise-induced anaphylaxis is also recognized.7
The last type of exercise-induced anaphylaxis described is medication-dependent or drug-dependent exercise-induced anaphylaxis. This category includes patients who develop the syndrome only after ingesting a specific medication and then exercising. The offending medications that have been reported include nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, antibiotics, and cold remedies.

Pathophysiology
In exercise-induced anaphylaxis, an exercise-induced lowering of the mast cell degranulation threshold occurs, which causes the release of histamine and other mediators and leads to the progression from pruritus and urticarial rash to the symptoms of anaphylaxis. In the food-dependent subset, this process is influenced by immunoglobulin E (IgE) mast cell sensitization by a known or unknown food. If the offending food is known, the amount of the specific food ingested has an effect on whether the patient has symptoms. The mechanism by which exercise lowers the mast cell degranulation threshold is unknown. Previous observations suggest that increased physical activity has a direct effect on mast cell releasability and does not result in an increased sensitivity to histamine.
Once the histamine and other mast cell mediators, including leukotrienes, are released, they cause the smooth muscle contraction responsible for the wheezing and GI symptoms. The histamine and other mast cell mediators also cause the vascular dilatation that leads to the escape of plasma into the tissues, causing urticaria and angioedema, and results in hypotension and shock.8,9

Frequency
United States
Prevalence is not well established. In one study, 9% of total episodes of childhood anaphylaxis and 20% of episodes in children older than 8 years were triggered by exercise.
International Case reports from Germany, Italy, Japan, United States, and Thailand are provided in the literature.

Mortality/Morbidity
Deaths of children have been reported, but they are rare. Infrequently, patients must alter their lifestyle and physical activity significantly; in some patients, the syndrome causes them to be unable to perform daily activities without the risk of anaphylactic syndrome.

Race
No racial predilection is known.

Sex
One study showed a slight male predominance, but most other studies show no overwhelming difference between sexes.

Age
Exercise-induced anaphylaxis has been reported from as young as 4 years into adulthood. In a study of 16 patients, 10 patients (63%) had onset in their teenage years.

Clinical History
Pediatric patients with exercise-induced anaphylaxis (EIA) typically are athletic or involved in school or otherwise organized sports, and they typically have a history of atopy and/or a family history of atopy or possibly of exercise-induced anaphylaxis.
Typical episodes occur after exercise on a particularly hot, humid, or cold day.
History of ingesting aspirin or other nonsteroidal anti-inflammatory drug (NSAID), a meal, or a specific food prior to exercising may be noted.

In women, the episodes can be more frequent and more severe before and during menstrual cycles.

The history of an episode most likely includes the initial pruritus and giant hives associated with the onset of the symptoms.

As the syndrome progresses, the patient may report nausea, cramping, diarrhea, vomiting, tinnitus, vertigo, pruritus, difficulty breathing, chest tightness, and wheezing; a syncopal episode may occur.

The history may be obtained from a paramedic who responded to the collapse of a child. In this case, the patient's history may include loss of consciousness or variable consciousness.
In several minutes or hours after the episode, the patient may report only a headache that can persist for as long as 3 days.

Physical
The physical examination should start with the airway, breathing, and circulation (ABCs).
The most emergent assessments are those of airway maintenance and level of consciousness. One must rule out laryngeal obstruction.
Simultaneously assess for hypotension.
The rest of the physical examination should include looking for the typical features of exercise-induced anaphylaxis, including urticaria and giant hives, angioedema, wheezing, and stridor.

Causes
Risk factors for exercise-induced anaphylaxis include personal or family history of exercise-induced anaphylaxis or atopy, male sex (in one study), exposure to food allergen, and extremes of weather.

Beta-blocker medications can aggravate anaphylactic episodes.

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I-Cell Disease (Mucolipidosis II)

Summary
I-cell disease is an example of the mucolipidoses, a
group of diseases which show features of both the
mucopolysaccharidoses and the sphingolipidoses. A
clinical description is given of a child suffering from
this condition. The diagnostic criteria are discussed,
as well as some of the necropsy findings.
THE genetic mucolipidoses are a group of diseases
which show the symptoms and signs of both the
mucopolysaccharidoses and the sphingolipidoses
(Table 1). Some of them such as Gm2 gangliosidosis
and infantile sulphatidosis are related to known
enzyme defects, but in others the cause is unknown.
Among the latter some of the affected children have
been described as Hurler's variants as they show
many of the features of Hurler's syndrome, but
excrete normal amounts of urinary mucopolysaccharides.

Case report
M.W. born 29 May 1967.
The child was referred to Booth Hall Children's
Hospital, Manchester, at the age of 2- years. She
had been born at home and was the second child in
the family, the older sibling having developed
normally. The pregnancy and birth were normal.
Multiple deformities had been recognized from birth
and she had been treated for a dislocation of the
right hip. At the time of her referral she could not
sit up herself and made no effort to stand. In general
development was around 8-9 months. Three times
in the past year the child had lost consciousness and
become cyanotic. There was no other past history or
family history of note.

On examination the unusual appearance of the
child was highly suggestive of gargoylism (Figs. 1
and 2). The bridge of the nose was broad and
flattened, the nostrils anteverted, and the tongue
was large. The eylids were puffy, the eybrows prominent,
and the cheeks were highly coloured. The
skin was coarsened. The abdomen was protuberant
and chest expansion was limited. There was flattening
of the left side of the skull and a fairly prominent
lumbo-dorsal kyphosis. There was fair movement in
the legs and feet, but the gluteal muscles appeared
to be weak. The right thumb was flexed in the palm
and could not be extended or abducted. Both hips
were held in about 45° of abduction by contractures,
probably in the abductor muscles. There was no
clouding of the cornea and the optic fundi appeared
normal. Muscle tone was slightly reduced, but the
tendon reflexes were present and equal. The liver
was enlarged one and a half finger's breadth, but the
spleen was not palpable, and there was no evidence
of cardiac involvement.

Over the next 2 years the child was greatly
troubled by chest infections, sometimes severe
enough to be classified as broncho-pneumonia. She
showed some evidence of development, and began
to stand in splints and seemed to benefit from wearing
a spinal jacket. She started to say a few words.
At the age of 2 years 7 months the patient weighed
7-05 kg (third percentile at this age 10-4 kg), and her
height was 70-1 cm (third percentile at this age
83 cm). The GQ on the Griffiths Mental Development
Scale was 27-2. X-ray of the skull showed very
marked asymmetry. On X-ray of the spine and pelvis
there was scoliosis convex to the left, and widening
of the interpedicular spaces in the lumbar spine
(Fig. 3). The posterior borders of the vertebral
bodies in the lumbar spine were concave. The proximal
ends of both the femora were constricted (Fig. 4).
The X-rays of the hands showed that the metacarpal
and the phalangeal medullary cavities were widened.
The cortices were very narrow and thin. The lower
ends of both the ulna and radius were tapered. The
EEG was characterized by a generalized increase of
slow wave activity. There were no epileptic discharges.
There was no excess excretion of mucopolysaccharides
in the urine. Abnormal vacuoles were
found in approximately 30% of mononuclear cells.
No evidence of metachromasia was found. Some
granules in the monocytes were Sudan black positive.


Bone marrow aspirations yielded dry taps. The urine
amino acid chromatogram was normal, as were the
liver function tests. On one occasion the plasma true
glucose was 20 mg/100 ml, but the presence of hypoglycaemia
was not confirmed on a number of other
occasions. Fibroblast cultures were attempted but
were unfortunately unsuccessful. Plans had been
made to repeat these cultures when the child was
admitted to hospital with broncho-pneumonia and
died soon afterwards. Permission for necropsy was
refused.

Discussion
The name 'I-cell disease' was derived from the
striking granular inclusions seen in the cultured
fibroblasts from children suffering from this syndrome.
From the few reported cases it seems likely
that the condition is inherited as an autosomal
recessive. Slow development is recognized early in
life, as well as the hypotonia. Congenital dislocation
of the hips, herniae, and hyperplasia of the gums are
also a feature. Recurrent upper respiratory tract
infection seems to be a characteristic feature, and
often a cause of death when complicated by congestive
heart failure. Development does not seem to
proceed further than sitting and standing without
support, and a few social responses such as smiling
and early vocalization. Unaided walking is not
accomplished, nor is toilet-training or self-feeding.
The affected children do not seem to survive more
than a few years (Leroy et al., 1971).
The appearance of the child becomes strikingly
similar to children with Hurler's syndrome. The
tongue is large, the earlobes fleshy, the forehead
high, the epicanthic folds prominent, the bridge of
the nose flat, the nostrils anteverted, and the upper
lip elongated (Sprangler & Wiedemann, 1970a). In
fact this is the diagnosis likely to be made. Apart
from the facies, dwarfed stature and severe retardation,
there is kyphoscoliosis, limited joint mobility
with claw hands, and sometimes enlargement of the
liver and spleen; but no clouding of the corneae.
The X-ray findings are somewhat similar as well.
There is marked periostieal new bone formation.
The tubular bones of the arms are short and plump.
The metacarpals are irregular and expanded and the
phalanges are bullet-shaped. The distal ends of the
radius and ulna are tilted. The vertebral bodies are
short and rounded and there may be beaking of the
last dorsal and first lumbar vertebrae. The ribs are
broad and the cranial vault is thickened. However,
the mucopolysaccharide excretion in the urine is
normal.
The peripheral lymphocytes and monocytes are
vacuolated and finely vacuolated cells are present in
the bone marrow. Cultured fibroblasts contain
coarse, regular, refringent inclusions staining blue
with toluidine blue, which are PAS and Sudan black
positive (Sprangler & Wiedemann, 1970b). Special
staining may also reveal metachromasia, indicating
that they contain mucopolysaccharides as well as
lipids (Matalon et al., 1968).
At necropsy foam cells are found in the endocardium,
lungs, spleen, liver, kidneys, adrenals and
aorta. Electron microscopy does not reveal the lipid
inclusions (zebra bodies) typical of Hurler's syndrome.
The lipid content of the tissues is generally
normal, ecept for some increase in total values
(Leroy et al., 1971). Liver acid P-galactosidase
activity has been found to be decreased, with hyperactivity
of a number of other enzymes (Tondeur
et al., 1971). Although the findings so far suggest a
storage disease involving both lipids and mucopolysaccharides
no definite cause can yet be suggested.
The differentiation from Hurler's syndrome is
made by the normal urinary excretion of mucopolysaccharides.
A somewhat similar clinical picture
occurs in mucolipidosis I or lipomucopolysaccharidosis,
but the features of gargoylism are not so marked
and the course of the disease is much more protracted.
Gm,-gangliosidosis, type I, has also been
referred to as pseudo-Hurler's syndrome because of
the appearance of the affected child, but the diagnosis
of this disease is confirmed by the abnormal
ganglioside pattern on thin layer chromatography of
brain extracts.


References
LEROY, J.G., SPRANGLER, J.W., FEINGOLD, M., OPITZ, J.M.
& CROCKER, A.C. (1971) I-cell disease: a clinical picture.
Pediatrics, 79, 360.
MATALON, R., CIFONELLI, J.A., ZELLWEGER, H. & DORFMAN,
A. (1968) Lipid abnormalities in a variant of the Hurler's
syndrome. Proceedings of the National Academy of Science,
59, 1097.
SPRANGLER, J.W. & WIEDEMANN, H-R. (1970a) The genetic
mucolipidoses. Neuropddiatrie, 2, 3.
SPRANGLER, J.W. & WIEDERMANN, H-R. (1970b) The genetic
mucolipidoses. Humangenetik, 9, 113.
TONDEUR, M., VAMAS-HURWITZ, E., MOCKEL-POHL, S.,
DERENME, J.P., CREMER, N. & LOEB, H. (1971) Clinical,
biochemical, and ultrastructural studies in a case of
chondrodystrophy presenting the I-cell phenotype in
tissue culture. Pediatrics, 79, 366

Information obtained from:
IINEIL GORDONM.D., F.R.C.P.