Presented at #EMconf on 3/16/2016 at Denver Health Medical Center

1. IMMUNE SYSTEM
DISORDERS
Zach Jarou, MD | @zachjarou @DenverEMed
Denver Health Residency in Emergency Medicine

2. 9.1 COLLAGEN VASCULAR DISEASE
9.1.1 Reynaud’s disease
9.1.2 Reiter’s syndrome
9.1.3 Rheumatoid arthritis
9.1.4 Scleroderma
9.1.5 Systemic lupus
erythematosus
9.1.6 Vasculitis
9.3 TRANSPLANT-RELATED
PROBLEMS
9.3.1 Immunosuppression
9.3.2 Rejection
9.2 HYPERSENSITIVITY
9.2.1 Allergic reaction
9.2.2 Anaphylaxis
9.2.3 Angioedema
9.2.4 Drug allergies
9.4 IMMUNE COMPLEX
DISORDERS
9.4.1 Kawasaki syndrome
9.4.2 Rheumatic fever
9.4.3 Sarcoidosis
9.4.4 Poststreptococcal
glomerulonephritis
THE EM MODEL
16 IMMUNE SYSTEM DISORDERS IN 4 CATEGORIES
abem.org/public/publications/em-model

3. THE EM MODEL
ROUGHLY CORRELATES TO GELL AND COOMBS’ CLASSIFICATION
• developed nearly 50 years ago to classify drug hypersensitivity reactions
• does not account for pseudo-allergic reactions (ie: direct histamine release
from hyperosmolarity of contrast media or red-man syndrome)
• allergies may be caused by more than one mechanism
(ie: contrast medium may also cause IgE-mediated mast cell degranulation)

4. ANAPHYLAXIS
DEFINITION, MECHANISM, COMMON ALLERGENS, TREATMENT,
BIPHASIC REACTIONS, DO STEROIDS HELP?, WILDERNESS BONUS EPI

5. ANAPHYLAXIS TYPE I HYPERSENSITIVITY
DIAGNOSIS
TWO OR MORE
ORGAN SYSTEMS
MECHANISM
TWO SEPARATE
EXPOSURES
*ANAPHYLACTOID = NON-IgE MEDIATED, TREATED SIMILARLY
absent 20% cases

6. ANAPHYLAXIS COMMON ALLERGENS

7. ANAPHYLAXIS TREATMENT

8. THE GOOD
alpha-1
• vasoconstriction, increased PVR/BP
• decreased mucosal/upper airway edema
beta-1
• increased chronotropy
• increased inotropy
beta-2
• decreased release of inflammatory mediators
from mast cells/basophils
• increased bronchodilation/vasodilation
THE BAD
common
anxiety, palpitations, pallor, tremor, fear,
restlessness, dizziness, headache
uncommon
ventricular arrythmias, angina, MI, pulmonary
edema, hypertensive urgency/emergency, ICH
ANAPHYLAXIS EFFECTS OF EPI
non-selective
alpha/beta agonist

9. ANAPHYLAXIS WHEN IM EPI FAILS
Step 1: Take your code-cart epinephrine.
It doesn’t matter if it is 1:1,000 or 1:10,000!
Step 2: Inject the full 1 mg into a 1,000 mL normal saline bag
(final concentration 1 mcg/mL).
Step 3: Run wide open until hemodynamics stabilize.
• temporizing measure
only, always call your
pharmacist!
• desired infusion rate 2-
10 mcg/min
• carefully titrate using
roller clamp based
upon response
PHARMACY INFUSION VS. DIRTY EPI DRIP

10. ANAPHYLAXIS ADJUNCTIVE AGENTS
• Epi is 1st
line, there is no equivalent substitute & no
absolute contraindications
• H1 blockers
– relieve cutaneous symptoms only
– no RCTs to support use during anaphylaxis
• H2 blockers
– in combination with H1 blockers, may help with cutaneous
symptoms (up to 10% of cutaneous histamine receptors
are H2), though no RCT for this or for use in anaphylaxis
• Bronchodilators
• Steroids
• Glucagon for beta-blocked patients (1-2mg q5min
IM/IV – may cause N/V/hyperglycemia)

11. ANAPHYLAXIS BIPHASIC REACTIONS
Biphasic Anaphylaxis: Review of Incidence, Clinical Predictors,
and Observation Recommendations
Immunology and Allergy Clinics of North America, 2007. PMID 17493505
Study # Biphasic # Total % Biphasic Notes
Popa & Lerner, 1984 3 N/A N/A coined term biphasic anaphylaxis
Stark & Sullivan, 1986 5 25 20% epinephrine was given SQ
Douglas et al, 1994 6 103 5.8%
Brady et al, 1997 2 67 3% first to include return ED visits
Brazil & MacNamara, 1998 6 34 18%
range 4.5 - 29.5 hours, biphasic
group initially required mean
1.2mg vs 0.6mg epinephrine
Lee & Greenes, 2000 6 105 6% first study of children
Forrest-Hay et al, 2003 9 91 9% 8 within 6 hours, 1 at 35 hours
Ellis & Day, 2004 20 103 19.4%
40% occurred 10+ hours later,
55% biphasic never received epi
(compared to 82% uniphasic)
Smit et al, 2005 15 282 5.3%
Hong Kong, mean 7.6 hours
(range of 1.2 - 22.5 hours)

12. ANAPHYLAXIS BIPHASIC REACTIONS
BACKGROUND
•biphasic anaphylactic reactions have been
reported to occur in as many as 20% of
anaphylactic reactions from 1 – 72 hours after
resolution of primary event
METHODS
•retrospective chart review of ~260k
presentations to ED of a tertiary care hospital
in Switzerland
– 1334 (0.5%) for allergic reactions
– 532 (0.2%) were for anaphylaxis
•outcomes
– clinically important biphasic reactions
– number of ICU transfers
– number of deaths within 10 days
Biphasic anaphylactic reactions: occurrence and mortality
Allergy, 2014. PMID 24725226
RESULTS
•of 532 cases of anaphylaxis
– 507 uniphasic
– 25 (4.6%) biphasic, of which 12
(2.3%) were clinically important
•no identifiable risk factors for biphasic
CONCLUSIONS
•biphasic reactions, especially clinically
important ones, are rare
•no mortality difference whether monitored
for >8 hours compared to less
•consider discharging patients after complete
resolution of anaphylactic reaction &
dispense with prolonged monitoring
532 cases, 2.3% rate of clinically important biphasic reactions

13. ANAPHYLAXIS BIPHASIC REACTIONS
BACKGROUND
•allergic reactions are common presentations
to the ED
•patients are often monitored for prolonged
periods to manage potential biphasic reactions
METHODS
•retrospective cohort of 2800 adults
presenting to two urban academic emergency
departments in Canada
•primary outcome = clinically important
biphasic reaction
•secondary outcome = mortality
Incidence of Clinically Important Biphasic Reactions in Emergency
Department Patients With Allergic Reactions or Anaphylaxis
Annals of Emergency Medicine, June 2014. PMID 24239340
RESULTS
•of 428k visits, 2800 (0.66%) were reviewed
(496 anaphylaxis, 2323 allergic reactions)
•185 (6.6%) had subsequent visit for allergic
symptoms
•5 (0.18%) had clinically important biphasic
reactions (2 during ED visit, 3 post-discharge)
•no fatalities
CONCLUSIONS
•clinically important biphasic
reactions/fatalities are rare
•prolonged routine monitoring of patients
whose symptoms have resolved is likely
unnecessary
2800 cases, 0.18% rate of clinically important biphasic reactions

14. ANAPHYLAXIS DO STEROIDS HELP?
BACKGROUND
•use of corticosteroids for allergic reactions in
ED has doubled in the past decade
METHODS
•retrospective cohort of 2700 adults
presenting to two urban academic emergency
departments in Canada
(473 anaphylactic)
•half got steroids (either in ED and/or 5 day
course), the other half received none
•primary outcome = repeat allergy-related ED
visit within 7 days
•secondary outcomes = mortality, clinically
important biphasic reactions
Emergency Department Corticosteroid Use For Allergy Or
Anaphylaxis Is Not Associated With Decreased Relapses
Annals of Emergency Medicine, March 2015. PMID 25820033
RESULTS
•no difference in repeat ED visits (n=170)
– 5.8% steroid group
– 6.7% non-steroid group
•no difference between subgroups initially
presenting with allergy vs. anaphylaxis
•5 clinically important biphasic reactions
– 4 steroid group (0.31% )
– 1 non-steroid group (0.071%)
•no deaths
CONCLUSIONS
•steroids do not reduce the risk of relapse for
patients presenting with allergic reactions or
anaphylaxis
2700 cases, steroids do not change rate outcomes

15. ANAPHYLAXIS READY FOR DISCHARGE
• EpiPen, the Kleenex of
epinephrine autoinjectors
• only comes in two-packs
• $1 worth of drug in a $415
package (after insurance
discounts)
• shelf-life 18 months
• Mylan Pharmaceuticals bought
EpiPen from German company
in 2007, revenue has increased
from $2 million to more than
$1 billion
• in France, 2x EpiPens cost $85
September 23, 2015

16. ANAPHYLAXIS WILDERNESS BONUS EPI

17. ANGIOEDEMA
ACE INHIBITOR INDUCED, HEREDITARY/ACQUIRED,
PATHOPHYSIOLOGY, TREATMENT OPTIONS

18. ANGIOEDEMA PRESENTATION
• consider fiberoptic naso-pharyngo-laryng-oscopy
• lip/tongue swelling may not accurately reflect
degree of airway edema
• localized swelling of subcutaneous
layer of skin OR submucosal layers
of respiratory/GI tracts (+/- hives)

19. ANGIOEDEMA TYPES
• allergic (with hives = mast cell/IgE-mediated)
• non-allergic (no hives = bradykinin-mediated)
– RAS blocker-induced (1/3 of all cases in the ED)
• renin-angiotensin-aldosterone system blockers (ie: ACEi)
• more than half of cases within 90 days but may take years
– hereditary (HAE): 3 types
• type I = low levels of C1 esterase inhibitor (80-85%)
• type II = normal level, decreased function C1-INH (15-20%)
• type III = estrogen induced
– acquired (AAE)
• rare, auto-antibodies against C1-INH
• a/w lympho-proliferative disease
– pseudoallergic
• NSAIDs, contrast, opioids
– idiopathic
• chronic, a/w chronic urticaria
• triggered by emotional/physical stress

20. ANGIOEDEMA PATHOPHYSIOLOGY
• HAE/AAE = uninhibited conversion of kininogen to bradykinin
• ACEi-AE = in some individuals, defect in other peptidases
leads to BK accumulation (as well as substance P)

21. ANGIOEDEMA TREATMENT OPTIONS
• HAE/AAE = FFP, recombinant C1-INH, ecallantide
• ACEi-AE = stop ACEi, icatibant for severe presentations

22. ANGIOEDEMA TREATMENT OPTIONS
A Randomized Trial of Icatibant in ACE-Inhibitor-Induced
Angioedema
New England Journal of Medicine, January 2015. PMID 25629740
BACKGROUND
•ACE-inhibitor angioedema accounts for 1/3 of
angioedema cases seen in ED
•life-threatening, no approved treatment
METHODS
•multicenter, double-blind, randomized phase
2 study
•30mg SQ icatibant, selective B2 antagonist
(compared to standard therapy of IV
prednisolone 500mg, plus clemastine 2mg – an
anti-histamine)
•primary end point = median time to complete
resolution of edema
RESULTS
•27 patients
•median hours to complete resolution
– icatibant = 8 hours (IQR, 3-16)
– control = 27 hours (IQR 20-48)
•median hours to onset of relief
– icatibant = 2.0 hours
– control = 11.7 hours
CONCLUSIONS
•time to onset of relief & complete resolution
of symptoms significantly shorter with
icatibant compared to glucocorticoid &
antihistamine
it works but with only 27 patients not powered for adverse effects,
major side effect: pain at injection site, debate: cost/indication

23. DRUG ALLERGIES
PENICILLIN-CEPHALOSPORIN CROSS-REACTIVITY,
CONTRAST MEDIA, LOCAL ANESTHETICS

24. DRUG ALLERGIES PENICILLINS-CEPHALOSPRINS
The use of cephalosporins in penicillin-allergic patients:
a literature review
Journal of Emergency Medicine, May 2012. PMID 21742459
BACKGROUND
•articles from the 1960s-70s report cross
reactivity rates of 8-18%
•the practice of avoiding cephalosporin
administration to PCN-allergic patients persists
despite low rate of cross reaction
METHODS
•literature review of all MEDLINE articles from
1950-2012 matching “penicillin$,”
“cephalosporin$,” “allerg$,”
“hypersensitivity,” “cross-react$” yielded 406
articles, 27 of which were reviewed
RESULTS
•little cross reactivity between B-lactam rings
themselves, instead related to R1 side chain
(amoxicillin/ampicillin)
•cross-allergy w/1st
-gen cephalosporins (OR
4.8) exists, negligible with 2nd
-gen
CONCLUSIONS
•even when using 1st
-gen cephalosporins or
those with similar R1 side chains, rate of
cross-reactivity is approximately 1%
•use of 3rd
/4th
generation cephalosporins or
those with dissimilar side chains has
negligible risk of cross allergy
PCN = most commonly reported medication allergy
Up to 90% of patients with reported allergy don’t have it.

25. DRUG ALLERGIES LOCAL ANESTHETICS
Diphenhydramine as an Alternative Local Anesthetic Agent
Journal of Clinical and Aesthetic Dermatology, October 2009. PMID 2923931
• anaphylaxis from local anesthetics is extremely rare,
most reactions are localized type 4 hypersensitivity
• when anaphylaxis does occur, usually esters, rarely amides
• no cross-reactivity between classes, however if patient reports true
anaphylaxis and you don’t know the class…
• or you don’t have access to lidocaine... or you’re near the toxic
dose of local anesthetic...

26. DRUG ALLERGIES CONTRAST MEDIA
The Relationship of Radiocontrast, Iodine, and Seafood Allergies:
A Medical Myth Exposed
Journal of Emergency Medicine, November 2010. PMID 20045605
• risk of reaction to contrast media ranges from 0.2% to 17%, low-osmolality
contrast available since 1988 w/less effects
• risk of reaction similar between those reporting allergy to seafood/shellfish and
other food allergies/asthma
• “iodine allergy” does not exist; no evidence that premedication works

27. IMMUNE SYSTEM
DISORDERS
Zach Jarou, MD | @zachjarou @DenverEMed
Denver Health Residency in Emergency Medicine