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Case #2 Anaphylaxis
June  2017

A 48-year-old male applies for life insurance. Records reveal that three years ago he had an anaphylactic reaction after being stung by a yellow jacket insect during a camping trip. Within 20 minutes of the sting, he developed symptoms of wheezing and shortness of breath as well as development of a pruritic, erythematous rash. He immediately obtained medical care at a local emergency room. He was described as being hypotensive as well as having significant respiratory symptoms. The event required both intravenous fluids and the administration of epinephrine. He was hospitalized and monitored in the intensive care unit for 24 hours. Since the event, he has undergone allergen-specific immunotherapy and has refrained from any further camping trips and generally avoids outside activities. He has had no other similar events, either prior or since. He is healthy other than some mild hypertension that had been treated with a beta blocker antihypertensive but changed to a thiazide diuretic after the event. Records show that he refills his antihypertensive medication regularly and also has refilled his prescribed emergency epinephrine injection on an annual basis.

What are the mortality considerations of a previous episode of anaphylaxis?

Anaphylaxis is an uncommon but potentially lethal event. First episodes of allergic reactions are difficult to predict, but once one anaphylactic reaction has occurred, subsequent episodes are possible and each subsequent event poses significant mortality risk. Underwriters are frequently asked to evaluate cases involving a previous anaphylactic event and predict future mortality risk.

Description

Anaphylaxis is typically described as an immunoglobulin E (IgE) mediated reaction after exposure to an allergen. Exposure is followed by an acute, multisystem response caused by the release of chemicals (enzymes, histamine, tryptase and others) from mast cells and/or basophils. These chemicals then cause severe inflammation in the tissues involved (e.g. skin, respiratory tract, gastrointestinal tract, cardiovascular system) which can be sudden and severe. There are approximately 40 different potential signs and symptoms associated with an anaphylactic reaction making diagnosis sometimes challenging. In addition, there are hundreds of known allergens. Frequently, the known allergens causing immunoglobulin E mediated reactions are lumped into several categories which include: foods, medications, insect bites, radiocontrast media, and other biological materials (e.g. vaccines).

Different triggers often affect different age groups (see Table 1). However, it should be noted that non-IgE dependent immunologic reactions (e.g. exposure to exercise, heat, or cold) can occur. They are associated with direct activation of the mast cells and/or basophils. They cause similar anaphylactic reactions. Unfortunately, it is difficult at times to identify the offending allergen. It is also difficult to identify other closely related allergens which might cause a similar, severe reaction. Making predictions even more difficult is the fact that subsequent anaphylaxis events can present in a completely different manner with different symptoms, signs or with a different time course. Thus, the individual who has experienced a previous anaphylactic reaction frequently finds themselves needing to be constantly prepared for another acute, severe reaction knowing that the next episode could be fatal.

Table 1 – MOST COMMON ANAPHYLAXIS CAUSES

Age Category ​ Cause
​Children ​Food-related
​20-39 year-olds ​Venom-related
​Older Adults​Medication-relate

 

Diagnosis
The diagnosis is established by a careful history of the clinical symptoms and signs. Criteria for the diagnosis were published by a group of experts in 2005 and 2006. The diagnosis of anaphylaxis is recommended when an individual fulfills one of three criteria (see table 2). Even though anaphylaxis is a clinical diagnosis, there are a couple of laboratory tests used which can be helpful. Elevated concentrations of either plasma tryptase or histamine are frequently associated with an anaphylactic event.

Table 2 – Making the diagnosis

​Anaphylaxis is highly likely when one of the following three criteria is met after allergen exposure:
  1. ​Acute onset of an illness with involvement of the skin, mucosal tissue, or both and at least one of the following:
    a. Respiratory compromise (e.g. dyspnea, wheeze)
    b. Reduced BP
  2. Two or more of the following that occur rapidly after likely allergen exposure:
    a. Skin-mucosal tissue involvement
    b. Respiratory compromise
    c. Reduced BP
    d. Persistent GI symptoms
  3. Reduced BP after known allergen exposure
    a. Infants and children: Low systolic BP (age specific) or >30% decrease in systolic BP
    b. Adults: Systolic BP<90 mm/Hg or >30% decrease from that person’s baseline

 

Treatment
Treatment of anaphylaxis involves both emergent treatment as well as long-term treatment:

Emergent treatment

  • Quick recognition of the event
  • Emergent administration of life-saving care (frequently involving the use of epinephrine)

Long-term treatment

  • A careful analysis of the causative agent
  • Education regarding the disorder
  • Recommendations for future avoidance (including similar potential causative agents) and
  • Guidance regarding emergent care for subsequent events. This frequently involves prescribing injectable epinephrine to have available at all times in the future

There are several barriers to successful treatment which challenge both clinicians and patients. These barriers, which impact adherence to and thus ultimate success of treatment, include:

  • The price of the medications
  • The need for regular replacement of the medication given the short shelf life
  • The fear of receiving epinephrine, especially repeat doses
  • The difficulty at times to identify the causative agent(s)
  • The inability to adequately avoid all causative agents even when identified
  • The logistic concerns with having epinephrine available at all times

Incidence of fatal anaphylaxis
Anaphylaxis can cause death. Most people experiencing anaphlaxis, however, do not die from the event. Death associated with an anaphylaxis reaction is less than 1 percent.

Based upon one study published in 2014 that analyzed data from 2006 to 2009, there are approximately 63-99 deaths annually in the United States from anaphylaxis. This calculates to a mortality rate ranging from 0.63 to 0.76 cases per million population. Interestingly, 77% of those deaths actually occurred in hospitalized patients. Similar fatal anaphylaxis incidence rates have been published from research in New Zealand and the United Kingdom. One caveat of these incidence studies, however, is the concern that some of the cases of fatal anaphylaxis are missed or misdiagnosed. This failure to recognize the cause of death can especially occur when the individual has significant comorbid conditions. One of the reasons for the inability to diagnose these events accurately is the rapid progression from exposure to death in some individuals, which creates an absence of specific findings, even at autopsy. In addition, specific definitive tests are frequently unavailable making the diagnosis difficult.
 
Etiology of fatal anaphylaxis
Death from anaphylaxis is typically from asphyxiation secondary to upper or lower airway obstruction or from cardiovascular collapse. Any of the long list of etiological agents can cause fatal anaphylaxis.

However, one study done in the United Kingdom attributed approximately half of the fatal reactions to medications or medical procedure injectable agents. Another one quarter of the deaths was from food. The final quarter was attributed to insect venom. Lack of timely administration of epinephrine has been associated with fatal anaphylaxis. Interestingly, in this United Kingdom study, epinephrine was used early in the fatal cases only 14% of the time. It was eventually used during the ultimate cardiac arrest in 62% of the cases, but was unsuccessful. This suggests the vital importance of not only early recognition of the event, but also the early administration of life saving medications.

The mortality risk can increase with certain situations (see Table 3).

Table 3 – Factors increasing mortality risk

The mortality risk increases with the following situations:
​Presence of comorbid conditions — persistent asthma or the presence of coronary artery disease are considered especially concerning
​Inability to adequately identify the causative agent and therefore avoidance activities are limited
​Noncompliance with allergen avoidance
​Failure to administer epinephrine in a timely manner
​Concurrent use of certain medications — beta blockers, angiotensin-converting enzymes, and alpha blockers all have been associated with lethal anaphylactic reactions
Of note, however, is that the severity of previous reactions does not necessarily predict the severity of future events as they can be more severe, less severe, or similar to previous episodes.


Finally, mortality risk can be mitigated with certain situations. Mortality risks can be significantly decreased with the following:

  • Education about recognition and appropriate emergent treatment of future anaphylactic episodes (e.g. developing and adhering to an anaphylaxis emergency action plan)
  • Administration of allergen-specific immunotherapy, which has been shown to almost completely prevent future anaphylactic reactions in those with Hymenoptera (e.g. wasps, yellow jackets, yellow hornets) induced events. This protection has been shown to be long lasting as well. Specifically, at least regarding incidence, it is estimated that 30-60% of adults who have previously had an anaphylactic reaction to hymenoptera insects will have another anaphylactic reaction to a subsequent sting. This risk drops to <5% for those who have completed venom immunotherapy
  • Desensitization to medications can be successfully accomplished in those individuals who have experienced reactions to a medication but who need that medication again in the future
    Optimal management of any comorbid conditions

Returning to the case

Fifty percent of fatal cases of insect-venom related anaphylaxis occur in those who have had a previous non-fatal event. Therefore, the fact that a 48-year-old male had a non-fatal first event doesn’t suggest a better prognosis. However, in this particular case, there are some very encouraging facts. The precipitating allergen has been identified in this case. The proposed insured has significantly mitigated future risk by minimizing his outdoor activities and has successfully been treated with immunotherapy. His antihypertensive medications have been adjusted to eliminate the beta blocker use. Finally, he has been educated as to emergent treatment of any future events and has demonstrated compliance with medication refills. The potential of future significant mortality risk from anaphylaxis appears to be very low.

References

Bilo, BM. Epidemiology of insect-venom anaphylaxis. Curr Opin Allergy Clin Immunol 2008 Aug.

Bilo, BM The natural history and epidemiology of insect venom allergy: clinical implications. Clin Exp Allergy 2009 Oct 39. 1467-76

Bock, S et al. Fatal anaphylaxis. UpToDate. Last accessed 5/23/2017

Jerschow, E et al, “Fatal anaphylaxis in the United States, 1999-2010: Temporal patterns and demographic associations.” J Allergy Clin Immunol. 2014 Dec; 134 (6) 1318-1328

Ma, L et al, “Case fatality and population mortality associated with anaphylaxis in the United States.” J Allergy Clin Immunol. 2014 Apr; 133 (4) 1075-83

Pumphrey, RS, “Lessons for management of anaphylaxis from a study of fatal reactions.” Clin Exp Allergy. 2000;30 (8): 1144

Sampson, HA et al, Second symposium on the definition and management of anaphylaxis: summary report -Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006, 117: 391-7

Tanno, LK et al. “Fatal anaphylaxis registries data support changes in the WHO anaphylaxis mortality coding rules.” Orphanet J Rare Dis. 2017 Jan 13;12(1) 8

Turner, P et al. “Increase in anaphylaxis-related hospitalizations but no increase in fatalities: An analysis of United Kingdom national anaphylaxis data, 1992-2012.” J Allergy Clin Immunol. 2015 April; 135 (4): 956-963