Anaphylaxis at autopsy
Anaphylaxis at autopsy
Roger W. Byard 0 1
0 School of Medicine, The University of Adelaide , Frome Road, Level 3 Medical School North Building, Adelaide 5005, SA , Australia
1 & Roger W. Byard
‘‘We can only say of him that his power to react has undergone a change’’
Clemens von Pirquet (1874–1929)
The concept of allergic reactions was first proposed by
Clemens von Pirquet when he was a resident in pediatrics
at the Universita¨ts KinderKlinic in Vienna. In 1906 he
published a short two page paper in which he suggested
that exposure to foreign material (antigens) alters the
immune system of an individual, and that while subsequent
exposure may induce immunity, it may also result in
hypersensitivity or altered reactivity. He coined the term
allergy from the Greek allos meaning ‘‘other’’ or
‘‘different,’’ and ergon meaning ‘‘energy’’ or ‘‘work’’ [
Although his work was recognized by the forensic
community, cases of fatal anaphylaxis are still not
commonly recorded in medicolegal practice despite increases
in potentially life-threatening food allergies in the
community over the past few years [
]. While it is difficult to
determine the precise prevalence of food allergy because of
the complex testing required, self-reported food allergies
have increased by a factor of 1.5 from 2001 to 2010 in the
United States. This is thought to be due to alterations in gut
commensal microbiota induced by increasing amounts of
antibiotics that are prescribed and that are present in certain
foods in industrialized countries [
hypersensitivity reactions have been responsible for as many as one in
200 adult presentations to emergency departments [
although recorded deaths from anaphylaxis remain rare
(0.12–1.06 deaths per million person-years) [
the apparent increase in numbers of allergic reactions in the
community raises the question as to why there has not been
a concomitant increase in cases of anaphylactic sudden
death being identified at the time of autopsy. Are the
allergies that are on the increase in the community not
potentially life-threatening, are they being more effectively
treated, or are not all cases that result in rapid deterioration
and death being identified? Possible reasons for the latter
may involve reduced suspicions on the part of examining
pathologists. This may be due to a number of factors
including absence of a typical presenting history, the
rapidity of some of these deaths, the non-specificity of
macroscopic and microscopic autopsy findings, and lack of
appropriate testing. The presence of potentially lethal
underlying medical diseases such as stenosing coronary
artery atherosclerosis in older individuals may also divert
attention away from a condition that may have far more
subtle manifestations [
Anaphylaxis refers to the cascade of events that may
follow exposure to a particular antigen causing an acute
multiorgan response, most often affecting the skin,
respiratory, cardiovascular, and neurological systems. It has
been defined as ‘‘a severe, life-threatening generalized or
systemic hypersensitivity reaction’’ [
]. Usually mediated
by immunoglobulin E (IgE), it represents a type I
hypersensitivity reaction to a foreign material such as
food (e.g., peanuts), medications (e.g., penicillin), or
animal venom (e.g., wasp or bee stings). This causes
release of chemical mediators from tissue mast cells and
basophils. Classically it follows prior exposure to a
particular allergen and results in flushing, angioedema,
pruritis, hypotension, arrhythmias, shortness of breath,
tachypnea, dysphagia, and reduced conscious state. These
features result from smooth muscle spasm and increased
The term anaphylactoid reaction was once used for
nonIgE-mediated reactions that involve IgG and immune
complex complement [
], although the clinical significance
of non-IgE-mediated anaphylaxis has been questioned [
It has been suggested that better terminology for this range
of events would be allergic (IgE-mediated and
non-IgEmediated), and nonallergic anaphylaxis (where mast cells
and basophils degranulate without the actions of
An age-related vulnerability exists with an increase in
food related allergies in the very young. One Australian
study showed that more than 10 % of 1-year-old children
had proven IgE-mediated allergies [
]. Children may,
however, grow out of their allergies, with 70–80 % of
children with reactions to milk or eggs being able to
tolerate these foods by the age of 16 years. In contrast,
only 20 % of children with peanut allergies and 10 %
with tree nut allergies will outgrow them [
]. It has been
suggested that the prevalence of allergic diseases is also
increasing in the elderly, which in combination with
significant comorbidities has increased the risk of fatal
There are a number of specific situations where the
possibility of anaphylactic reactions should be considered
in cases of sudden death. One example involves outdoor
workers where there is the possibility of exposure to
workrelated allergens. This may involve animal bites or insect
stings. For example, deaths in snake handlers are more
likely to be due to anaphylaxis rather than to the direct
toxic effects of reptile venom [
]. Unfortunately insect
stings or snake bites may be quite difficult to identify at
autopsy and so may not be considered or carefully looked
for in the absence of a history. Other usually less severe
occupational exposures involve vegetable allergens, food
products, and drugs [
]. Perioperative anaphylaxis should
be thought of in deaths that occur around the time of
surgery as it has been identified in 1/10,000 of patients
undergoing surgery, most often related to exposure to
neuromuscular blockers [
Death from anaphylaxis usually results from a
combination of factors including upper airway obstruction from
mucosal edema, asphyxia from bronchospasm, and shock
due to massive fluid shifts. Hemorrhagic and
thromboembolic phenomena may also occur [
]. Symptoms develop
quite quickly after exposure to a particular antigen (within
20 min) in 86 % of cases, with 33 % of deaths occurring
within 30 min, and 50 % within 1 h [
]. There are
however numerous problems that arise in establishing the
diagnosis of anaphylaxis at autopsy as it remains
essentially a clinical diagnosis with features that may either have
never developed, or not persisted until the time of
postmortem examination. For example, skin changes are either
very subtle or absent in as many as 20 % of cases [
Ideally cutaneous swelling, upper airway edema, and
hyperinflation of the lungs with mucus plugging may be
observed. Airway swelling may be generalized or limited
to the oropharynx, nasopharynx, epiglottis, larynx, or upper
trachea, but it may also be absent [
]; e.g., no typical
macroscopic features were present in 41 % of cases at
autopsy in one series attributed to the rapidity with which
such deaths may occur [
]. Microscopic evaluation of
upper airways may show edema with an infiltrate of
eosinophils and immunohistochemical staining of tissue
sections may reveal tryptase, a mast-cell-specific enzyme.
While excluding other causes of death is always necessary,
it is also very important not to confuse an illness or
condition that somebody may simply have died with, with
something that they may have actually died from.
Postmortem testing of sera is an extremely useful
diagnostic step with elevated levels of allergen-specific IgE
indicating antemortem sensitization, and a tryptase level of
10 lg/l, or more, being a sensitive (86 %) and specific
(88 %) marker. Other authors have taken a tryptase level of
[20 lg/l [
]. It should be noted, however, that
elevated tryptase levels have been found in deaths due to
trauma, SIDS, and heroin overdose. This has resulted in the
suggestion that perhaps some of these deaths have had an
allergic component. Serum tryptase and IgE levels may
also increase with increasing postmortem interval .
For a pathologist to suspect the possibility of fatal
anaphylaxis there usually needs to be a history of exposure
to an antigen, followed by shortness of breath and collapse,
in a previously sensitized individual. Without these
prompts the non-diagnostic findings at autopsy will
continue to make this a problematic diagnosis. It is, therefore,
possible, as with other subtle immunological, biochemical,
and metabolic conditions, that not all cases will be
identified at autopsy giving us a potentially skewed perception
of the role that anaphylaxis may play in contemporary
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