SUBJECT FORENSIC SCIENCE

Paper No. and Title PAPER No.14: Forensic Medicine

Module No. and Title MODULE No.32: Anaphylactic Death

Module Tag FSC_P14_M32

FORENSIC SCIENCE PAPER No.14: Forensic Medicine

MODULE No.32: Anaphylactic Death
 TABLE OF CONTENTS

1. Learning Outcomes
2. Introduction
3. Etiology
4. Epidemiology
5. Pathophysiology
6. Post-mortem Diagnosis
7. Summary

FORENSIC SCIENCE PAPER No.14: Forensic Medicine

MODULE No.32: Anaphylactic Death
 1. Learning Outcomes

After studying this module, you shall be able to know-

 What is anaphylactic death, its etiology and the various risk factors related to it
 Pathophysiology of anaphylaxis
 Post-mortem diagnosis of anaphylactic deaths

2. Introduction

ANAPHYLAXIS: Anaphylaxis is a rapid-onset, potentially life-threatening systemic

allergic reaction that can affect people of any age or sex. Anaphylactic attack requires an
immediate shifting of the patient to the Casualty department where adrenaline needs be
injected. If anaphylaxis isn't treated at once, it can lead to coma or even death. Acute
allergic reaction is an uncommon but well recognized cause of sudden death. The exact
incidence of fatal outcome is unknown but roughly estimated to be about 1% of total
incidences of anaphylaxis per year.

Possible under-diagnosis: In humans, fatal anaphylaxis is difficult to study because it is

rare, unpredictable, and often un-witnessed. Fatal anaphylaxis may be under diagnosed
because of the absence of specific findings at autopsy and lack of definitive diagnostic
laboratory tests.

3. Etiology

Fatal anaphylaxis can occur following a variety of triggers, although the most common
culprits are medications, foods, and insect stings. Approximately one-half of all
anaphylactic fatalities each year in the United Kingdom register have been attributed to
medications or agents administered during medical procedures (such as contrast media).
Reactions to foods and insect venoms each accounted for nearly a quarter of the total
cases, with other causes accounting for the remaining cases.

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MODULE No.32: Anaphylactic Death
 1. Medications: Beta-lactam antibiotics (e.g. penicillins and cephalosporins) appear
to cause more fatalities than other drugs. Multiple other agents such as
Radiocontrast agents, neuromuscular blockers, anaesthetic agents, Allergen
immunotherapy and other antibiotics have been implicated in smaller numbers of
cases.
2. Foods: Peanuts and tree nuts account for the majority of food-induced fatalities.
Cow's milk and seafood are also leading causes of severe and fatal reactions. A
variety of other foods have been implicated less commonly.
3. Insect stings: Stings of hymenoptera species (yellow jacket, honey bee, wasp,
hornet, and imported fire ants) are one of the three leading causes of fatal
anaphylaxis. Men are more often stung by insects, perhaps due to higher rates of
outdoor occupations.
4. Other causes: Other reported causes of fatal anaphylaxis include latex, rupture of
a hydatid cyst, infestation with the parasite Tinea solium and dental impression
material. In some cases, no cause can be identified and the etiology is designated
idiopathic.

Risk Factors
Concomitant asthma is a significant risk factor for fatal anaphylaxis, particularly for
adolescents with food allergy. Older victims of anaphylaxis (from all causes) often have
underlying cardiopulmonary conditions. Other possible risk factors include delayed or no
administration of epinephrine and upright posture during anaphylactic attack.

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MODULE No.32: Anaphylactic Death
 4. Epidemiology
Adolescents and young adults are at highest risk for fatal anaphylaxis induced by foods.
Middle-aged and older adults account for most fatalities from venom and medication-
induced reactions. There are no clear differences between genders or among racial
groups.
 Location: Studies reveal that fatal food reactions occur in the patient's home, the
homes of friends, restaurants, work or office settings, and schools. Fatal stings can
be sustained outdoors (more often) or indoors. Medication-induced fatal
anaphylaxis often occurs in a medically-supervised setting.
 Timing and Allergen Dose: Fatal anaphylaxis typically results in death within 30
to 60 minutes of ingestion or exposure to allergen. It seems logical that the higher
the allergen dose, the more rapid and severe the reaction, although patients may
have very different threshold levels beyond which they will experience
anaphylaxis. The amount of allergen is usually unremarkable (e.g., variable
amounts of food, one insect sting, a normal dose of medication).

5. Pathophysiology
In 1902, in a study involving protocols for immunizing dogs with jellyfish toxin the
anaphylaxis phenomenon was first observed and described. The injection of small
amounts of toxin in some animals rather than generating protection precipitated the rapid
onset of fatal or near-fatal symptoms. The authors named this response ‘anaphylaxie,’
which is derived from the Greek words a- (against) and phylaxis (immunity or
protection).
Anaphylaxis is a severe allergic reaction of rapid onset that occurs due to the release of
inflammatory mediators and cytokines from mast cells and basophils, typically due to
an immunologic reaction but sometimes non-immunologic mechanism.

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MODULE No.32: Anaphylactic Death
 (a) Immunologic mechanism:
In the immunologic mechanism, immunoglobulin E (IgE) binds to the antigen (the
foreign material that provokes the allergic reaction). Antigen-bound IgE then
activates FcεRI receptors on mast cells and basophils. This leads to the release of
inflammatory mediators such as histamine, tryptase, chymase, heparin, histamine-
releasing factor, and platelet-activating factor (PAF). Cellular activation also stimulates
the production of lipid-derived mediators such as prostaglandins and leukotrienes. These
mediators subsequently increase the contraction of bronchial smooth muscles,
trigger vasodilation, increase the leakage of fluid from blood vessels, and cause heart
muscle depression.

(b) Non-immunologic mechanism:

Non-immunologic mechanisms involve substances that directly cause

the degranulation of mast cells and basophils. These include agents such as contrast
medium, opioids, temperature (hot or cold), and vibration.

Organ System Involvement in Anaphylaxis: The predominant shock organs are the heart,
lung, and vasculature, and fatalities are divided between circulatory collapse and
respiratory arrest.

 Cardiovascular System Involvement: Anaphylaxis is associated with

myocardial depression, arrhythmias, and myocardial ischemia. Contributing
factors include direct mediator effects on the myocardium, exacerbation of pre-
existing myocardial insufficiency by the hemodynamic stress of anaphylaxis, and
exogenous or endogenous epinephrine.

 (b) Respiratory System Involvement: Anaphylaxis may affect any part of the
respiratory tract, causing bronchospasm and mucus plugging in the smaller
airways, and laryngeal edema and asphyxiation in the upper airway. Asphyxiation
typically occurs rapidly after allergen exposure, with death occurring within one
hour in many cases. Severe bronchospasm during anaphylaxis characteristically
develops in individuals with pre-existing asthma.

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MODULE No.32: Anaphylactic Death
 Evidence suggests that during anaphylaxis, peripheral tissues continue to consume
oxygen at relatively high rates, and that this, in combination with peripheral
vasoconstriction and decreased perfusion, leads rapidly to anaerobic metabolism and end-
organ damage.

Differential Diagnosis: Sometimes can be difficult to distinguish anaphylaxis

from asthma, syncope, and panic attacks. In asthma there is neither itching nor
gastrointestinal symptoms, however in syncope there occurs pallor and not a rash
whereas a panic attack may present with flushing but does not have hives.

Management

Anaphylaxis is a medical emergency that may require resuscitation measures such

as airway management, supplemental oxygen, large volumes of intravenous fluids, and
close monitoring. Administration of epinephrine is the treatment of choice
with antihistamines and steroids often used as adjuncts.

Cause of Death
Respiratory arrest and/or shock with cardiovascular collapse are responsible for most
fatalities.
The cause of death appears to be determined, at least in part, by the type of allergen. In a
review of 56 cases of fatal anaphylaxis by Pumphrey and Roberts, for which autopsy data
were available, all food-induced reactions involved difficulties in breathing, and
respiratory arrest was the cause of death in 13 of 16 cases. In contrast, shock without
respiratory compromise was the presentation in most cases of venom- or medication-
induced anaphylaxis. This correlation between allergen type and mechanism of death has
been noted in several studies. In a very small number of cases, massive epinephrine
overdose or disseminated intravascular coagulation appeared to be the immediate cause
of death.

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MODULE No.32: Anaphylactic Death
 6. Postmortem Diagnosis

Sudden anaphylactic deaths that occur outside hospital, or in the emergency room, or
during medical treatment are subjected to forensic autopsies. These cases are a source of
frustration to the forensic pathologist because the diagnosis of anaphylactic shock is one
of exclusion and has been based solely on circumstantial evidence, e.g. in deaths
immediately after ingestion of certain foods or taking medications known to cause allergy
or after stings (e.g., wasp or honey bee stings). The diagnosis of fatal anaphylaxis is
determined by the clinical presentation and historical information. Autopsy findings and
laboratory testing may support the clinical impression, although they are not necessary or
sufficient, in isolation, to make the diagnosis. In cases of sudden death of uncertain cause,
femoral venous blood can be collected and the serum can be separated and frozen for
later analysis.
Autopsy findings: Many victims have no distinguishing gross pathologic features at
autopsy, particularly if shock develops rapidly. When present, however, findings include
upper airway edema, mucus plugging and hyperinflation of the lungs, and cerebral
edema.
In the series of 56 cases reviewed by Pumphrey and Roberts, all individuals collapsed
after allergen exposure, and 23 had a documented asthmatic component. Dermatologic
signs and symptoms were uncommon. The following gross findings were reported:
o Laryngeal or pharyngeal edema (41%),
o Hyperinflation of the lungs and/or mucus plugging (27%),
o Cerebral edema, suggesting cerebral hypoxia (27%),
o Petechial hemorrhages in the airway mucosa, suggesting asphyxiation
(18%)
o Cutaneous erythema or urticaria (5%).

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MODULE No.32: Anaphylactic Death
 In another series review of 92 deaths from Ontario, Canada, the autopsies were
performed in 65 of the documented deaths (71%). The commonest reported finding on
autopsy was pulmonary congestion and edema (60%), followed by Upper airway edema
(46%). Cerebral edema, Congestion of liver and spleen, Petechial haemorrhage & Mucus
plugging of bronchi and hyperinflation each were found in approximately 15% cases.
Vomiting was reported in 8% cases only.
Amongst 30 venom related deaths (33%), evidence of insect sting was found in 12% of
cases. Severe edema was found in 46% of those with upper airway edema and 11% with
lower airway findings.
In cases where anaphylaxis to food is suspected at the time of death, the pathologist can
be asked to preserve some of the stomach contents for later analysis for suspected food
allergens.
Thus, autopsy findings in suspected anaphylactic deaths are variable and appear to
depend on the type of allergen and the route of administration as well as the time between
initiation of the allergic reaction and death.
Serum tests: Blood collected during or shortly after the event may be analysed
retrospectively for the mast cell-derived mediator tryptase, and for evidence of
immunoglobulin E (IgE) to the suspect allergen.
Histamine, serotonin, and heparin are substances stored in mast cells. The biochemical
and physiological effects of these substances have been known since long., histamine has
been used to show mast cell activation in in-vivo studies. However, histamine is rapidly
metabolized post-mortem. Recently neutral proteases have been found more stable and
reported to be located exclusively in mast cells and basophils.

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MODULE No.32: Anaphylactic Death
 Tryptase a the neutral protease, is the protein product produced by human mast cells
found in abundance. Mature β-tryptase is stored in secretory granules. It is an
enzymatically active tetramer found as a complex form with heparin until the cells are
activated to degranulate and release the protease-proteoglycan complex; α-Tryptase is the
predominant form of tryptase detected in normal serum and is markedly elevated in
patients with systemic mastocytosis. The release of β--tryptase into the circulation serves
as a clinical marker of mast cell activation.
Tryptase is a mediator released by mast cells upon activation and is relatively specific to
this cell type, although basophils also make a small amount. Any elevation is consistent
with anaphylaxis. Tryptase levels that are within normal limits do not exclude the
diagnosis. Tryptase is seldom elevated in food-induced anaphylaxis.

Quantitative IgE immunoassays may be helpful in detecting the presence of allergen-

specific IgE in the victim's serum as a means of confirming that the patient was allergic
to the allergen in question. Serum IgE levels do not change substantively as a result of
anaphylaxis. Positive tests for allergen-specific IgE suggest the presence of sensitization.
Negative assays do not exclude sensitization.
In one retrospective review by Pumphrey and Roberts, there were 56 cases of fatal
anaphylaxis in which autopsy information was available. Of these, 21, 19, and 16
fatalities were due to medications, insect venoms, and food allergies, respectively.
Laboratory test results were not available in most cases. However, in the 16 cases of fatal
anaphylaxis (due to a variety of agents) in which tryptase levels were measured,
elevations were found in 14. In a series of 25 selected cases of fatal anaphylaxis reviewed
by Greenberger et al, serum total tryptase concentrations were elevated in four of seven
cases tested.

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MODULE No.32: Anaphylactic Death
 In a Canadian review of 92 deaths in 26 years from 1986 to 2011 related to anaphylaxis,
causes of death, in order of decreasing frequency were found as due to food (40 cases),
insect venom (30 cases), iatrogenic (16 cases), and idiopathic (6 cases). Various factors
associated with fatal anaphylaxis were found as: delayed epinephrine administration,
asthma, allergy to peanut, food ingestion outside the home, and teenagers with food
allergies.
In many cases of fatal anaphylaxis no specific findings are present at autopsy. This is
particularly likely after reactions that caused rapid onset of shock. In the presence of a
typical history of incidence, the absence of specific postmortem findings does not
eliminate the diagnosis of anaphylactic death Tests for specific IgE and mast cell tryptase
might help to determine whether anaphylaxis is the cause of death, but are not often used.
These tests should be performed in all cases with a suggestive clinical history and no
specific findings at autopsy. Furthermore, the possibility of anaphylaxis should be
considered in all cases of sudden unexpected death with absent postmortem findings;
femoral vein blood should be sampled, and the separated serum frozen, to enable later
testing for specific IgE antibodies and mast cell tryptase. The results of these assays
should be interpreted in the context of clinical history and postmortem findings.

Post-mortem diagnosis of anaphylactic death is very difficult and it’s possible only after
excluding every other cause of death. The diagnosis of fatal anaphylaxis is based upon
clinical course and historical information, supported by laboratory and autopsy findings.
Femoral venous blood can be collected and the serum separated and frozen for later
assays of tryptase and allergen-specific immunoglobulin E (IgE). Victims of fatal
anaphylaxis may show no distinguishing gross pathologic features at autopsy, possibly
because death can ensue so rapidly. In the presence of a typical clinical history, absence
of postmortem findings does not exclude the diagnosis of anaphylaxis.

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MODULE No.32: Anaphylactic Death
 7. Summary

 Anaphylaxis is a rapid-onset, potentially life-threatening systemic allergic

reaction that can affect people of any age or sex.
 Fatal anaphylaxis can occur following a variety of triggers, although the most
common culprits are medications, foods, and insect stings.
 Adolescents and young adults are at highest risk for fatal anaphylaxis induced by
foods.
 Postmortem diagnosis of anaphylaxis is extremely difficult and possible only after
excluding other causes and obtaining clear history.
 Histamine, Serotonin and Tryptase estimations are helpful in confirmation of
anaphylactic death.
 Quantitative IgE immunoassays may be helpful in detecting the presence of
allergen-specific IgE in the victim's serum as a means of confirming that the
patient was allergic to the allergen in question.

FORENSIC SCIENCE PAPER No.14: Forensic Medicine

MODULE No.32: Anaphylactic Death