Differential Diagnosis

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Ana_ddx.png
Other:
  • Histamine Intolerance
  • Idiopathic anaphylaxis is fairly common in adults and can account for 60% of cases
  • MSG ingestion has been reported to cause chest pain, facial burning, flushing, paresthesias, sweating, dizziness, headaches, palpitations, nausea, and vomiting in susceptible individuals



Diagnosis


Essential History

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Clinical Symptoms

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WAO Criteria (2011)

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Hypotension in Children
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Biphasic Anaphylaxis
  • Anaphylaxis in which symptoms recur within 1-72 hours (usually within 8-10 hours) after the initial (first phase) symptoms have resolved, despite no further exposure to the trigger
  • Occurs in up to 23% of adults and up to 11% of children with anaphylaxis
  • Failing to treat initial symptoms with epinephrine increases risk for biphasic anaphylaxis

Protracted Anaphylaxis
  • Anaphylaxis episode that lasts hours to days without resolving completely
  • Seems to be rare


WAO SCIT Systemic Reaction Grading System

Grade 1
2
3
4
5
Symptoms of 1 organ system present:

Cutaneous
  • Generalized pruritus, urticaria, flushing, or sensation of heat or warmth
OR
  • Angioedema (not laryngeal, tongue or uvular)
OR
Upper respiratory
  • Rhinitis - (eg, sneezing, rhinorrhea, nasal pruritus and/or nasal congestion)
OR
  • Throat-clearing (itchy throat)
OR
  • Cough perceived to originate in the upper airway, not the lung, larynx, or trachea
OR
Conjunctival
  • Erythema, pruritus or tearing
OR
Other
  • Nausea, metallic taste, or headache
Symptoms >1 organ system present
OR
Lower respiratory
  • Asthma: cough, wheezing, shortness of breath (eg, <40% PEF or FEV1 drop, responding to an inhaled bronchodilator)
OR
Gastrointestinal
  • Abdominal cramps, vomiting, or diarrhea
OR
Other
  • Uterine cramps
Lower respiratory
  • Asthma (eg, 40% PEF or FEV1 drop NOT responding to an inhaled bronchodilator)
OR
Upper respiratory
  • Laryngeal, uvula, or tongue edema with or without stridor
Lower or upper respiratory
  • Respiratory failure with or without loss of consciousness
OR
Cardiovascular
  • Hypotension with or without loss of consciousness
Death-----
Note
  • Patients may also have a feeling of impending doom, especially in grades 2, 3, or 4.
  • In children, behavior changes may be a sign of anaphylaxis; eg, becoming very quiet or irritable and cranky.
  • Symptoms occurring within the first minutes after the injection may be a sign of severe anaphylaxis; mild symptoms may progress rapidly to severe anaphylaxis and death.
How to Score
  • The final grade is determined after the event is over
  • Grade (from table above) includes the following suffixes:
    • Onset of systemic reaction after injection:
      • ≤5 min - a
      • >5 to ≤10 min - b
      • >10 to ≤20 min - c
      • >20 min - d
    • and whether epinephrine was not administered:
      • epinephrine not administered - z
    • Also include comment regarding initial symptom of systemic reaction and time of onset after injection.
    • Example grade: "grade 2az; rhinitis; 10 minutes"
  • If patient's symptoms are not included in the table above or if the differentiation between a true systemic reaction and vasovagal (vasodepressor) reaction is difficult, include comment with grade, as appropriate.

Grading System for Hypersensivity Reactions (Brown)

Brown HSR grading.png

Lab Testing

Test
Comment
When to draw
Lab details
Total tryptase
(serum, plasma)
  • Total = mature + pro forms of α/β-tryptases
  • Schwartz
    • Peak elevation above baseline 15-60 min after onset of anaphylaxis; declines to baseline with a t1/2 of ∼2 h
    • Comparing acute and baseline levels improves sensitivity and specificity
    • Draw within the first 1-3 h after symptom onset if possible; samples collected <15 min or >4 h after symptom onset are less likely to be informative
  • Fleischer
    • Serum tryptase t1/2 is 1.5-2 h and peaks post mast cell degranulation in 15-120 minutes
  • Practice parameter
    • Levels peak 60-90 min after the onset of anaphylaxis and persist to 6 h
    • Ideally the measurement should be obtained between 1-2 h after the initiation of symptoms
  • Castells: some evidence to suggest that rheumatoid factor (IgM) interferes with the tryptase assay to yield falsely elevated levels; newer assays avoid this problem
  • Elevated tryptase levels may also be seen in renal failure or insufficiency, myocardial infarction, amniotic fluid embolism, SIDS, trauma, certain hematologic disorders (e.g. chronic eosinophilic leukemia, myelodysplastic syndromes, acute leukemias), bone marrow suppression states, chronic helminth infection, any disease causing endogenous stem cell factor elevation, with levels typically <40 ng/mL; 1-3% of healthy population may have tryptase >15 ng/mL
  • Systemic steroids can suppress tryptase levels to normal range in patients with mastocytosis
  • Median serum tryptase levels are higher in early infancy (even higher if atopic, median 14.2 mcg/L) and gradually fall to pediatric/adult levels by 9-12 months
  • Simons: Normal total tryptase levels cannot be used to refute the diagnosis of anaphylaxis because they are seldom increased in patients with food-induced anaphylaxis or those in whom blood pressure remains normal during anaphylaxis
Draw acute level 1-3 h after symptom onset
(Avoid drawing <15 min or >4 h after onset)

Draw baseline level >24 h after symptoms resolved
  • Phadia AB
  • Blood can be drawn using normal technique. Collect blood for serum (red top tube) or plasma (tube with heparin, citrate or EDTA). A minimum of 1 mL is required.
  • Serum or plasma should be placed on ice and frozen as soon as possible. Samples should be shipped frozen by overnight courier if the assay cannot be performed on site.
Mature tryptase
(serum, plasma)
  • Mature β-tryptase
  • Peaks 15-60 min after the onset of anaphylaxis and then declines with a t1/2 of ∼2 hours
  • Total/mature tryptase ratio >20 suggests mastocytosis
As above
  • Available at VCU
  • Lawrence B. Schwartz, M.D., Ph.D.
    P.O. Box 980263
    Richmond, Virginia 23298-0263
    Phone: (804) 828-9685
    E-mail: lschwart @ vcu.edu
Histamine
(plasma)
  • Schwartz
    • Peaks 5-10 min after symptom onset and declines to baseline by 15-30 min
    • Level may be falsely elevated by drawing blood through a small-bore needle under vacuum or when blood clots (due to basophil histamine release)
    • Draw as soon as possible after symptom onset: preferably within 15 min; samples collected >30 min after symptom onset are less likely to be informative
  • Simons
    • Obtain within 15 minutes to 1 hour of symptom onset; histamine levels peak within 5-15 min of symptom onset and decline to baseline by 60 min
    • Serum plasma histamine levels that are within normal limits do not rule out the clinical diagnosis of anaphylaxis
  • In one study, histamine was more sensitive than tryptase in helping to confirm anaphylaxis
As soon as possible after symptom onset, (ideally within 30 min)
  • Most commercial labs
  • Pull blood manually (DO NOT use vacuum tubes) under gentle pressure through a 20 gauge or larger needle into a syringe containing either citrate or EDTA.
  • Should be measured in plasma only (not serum)
  • The anticoagulated blood should be placed on ice (4 deg C) and centrifuged to separate plasma from cells as soon as possible, and then frozen until ready to be analyzed.
Histamine
(24 h urine collection)
  • May be elevated up to 24 h after symptom onset; histamine-containing foods and histamine-producing enteric bacteria may raise level
  • Collection should begin as soon as possible after the acute event
  • May be helpful if elevated, but normal levels do not exclude mast cell activation
  • Greenberger: urine histamine levels may be increased even with uvula or tongue angioedema
  • Level <30 ng/mL considered normal
24 h urine collection starting as soon as possible after symptom onset

N-methylhistamine
(plasma, urine)
  • Histamine metabolite
  • May be elevated up to 24 h after symptom onset; histamine-rich foods and histamine-producing enteric bacteria may raise level
  • Urine level may be helpful if elevated, but normal levels do not exclude mast cell activation
Within 24 hours of symptom onset

May also obtain as 24 h urine collection starting as soon as possible after symptom onset

N-methylimidazole acetic acid
(plasma, urine)
  • Metabolite of N-methylhistamine
  • May be elevated up to 24 h after symptom onset; histamine-rich foods and histamine-producing enteric bacteria may raise level
Within 24 hours of symptom onset

Free metanephrine
(plasma)
  • Elevated in pheochromocytoma, not systemic anaphylaxis
  • Useful in ruling out a paradoxical response to a pheochromocytoma


Fractionated metanephrines and catecholamines
(24 h urine)
  • Highly sensitive and specific diagnostic test for pheochromocytoma


Prostaglandin D2
(urine)
  • Marker of mast cell degranulation
  • Patients taking NSAIDs for any reason should discontinue them if feasible prior to collection of urine, because NSAIDs block PGD2 synthesis
  • Reported that some patients with systemic mastocytosis have mast cell activation manifesting as selective excessive release of PGD2 (treatable with NSAIDs but not antihistamines)
24 hour urine, starting at symptom onset

11β-prostaglandin F2α
(urine)
  • PGD2 metabolite
  • Patients taking NSAIDs for any reason should discontinue them if feasible prior to collection of urine, because NSAIDs block PGD2 synthesis
24 hour urine, starting at symptom onset

Serotonin
(serum)
  • Elevated in carcinoid syndrome, not systemic anaphylaxis


5-hydroxyindoleacetic acid, 5-HIAA
(urine)
  • Serotonin metabolite
  • Elevated in carcinoid syndrome, not systemic anaphylaxis
  • Carcinoid tumors release many mediators in an episodic fashion, some of them being also released by mast cells on activation (e.g., histamine, prostaglandins) which partly explains their similar clinical features (flushing, bronchospasm, diarrhea, hypotension) and that they can both respond to antihistamines
  • 24-hour urine preferred because level can vary during the day
  • Random urine sample along with a urine creatinine level is less sensitive but may be obtained when a 24-hour sample is not feasible

Chromogranin A, CgA (serum)
  • CgA is a protein found in and released from neuroendocrine cells. Blood CgA level may be elevated in pheochromocytoma and carcinoid syndrome.


Vasointestinal polypeptide (VIP) hormone panel (serum)
  • Pancreastatin
  • Pancreatic hormone
  • Vasoactive intestinal peptide
  • Substance P
  • Neurokinin A
  • Useful to rule out VIP–secreting GI tumor or a medullary carcinoma of the thyroid, which also can secrete vasoactive peptides


Calcitonin level
(serum)
  • Useful to rule-out medullary thyroid carcinoma
  • Medullary thyroid carcinoma can cause flushing and diarrhea in patients with advanced disease, at which time they usually also show signs of local involvement and have an increased serum calcitonin level


IgE anti-alpha-gal





Serum Tryptase Levels


Total (ng/mL)-----
Mature
Ratio---
Normal
<11.5
<1
NA
Anaphylaxis
11.5
>1
10
Mastocytosis-----
20
± elevated-----
20
  • Standard clinical assay measures total tryptase (sum of pro and mature forms of alpha and beta tryptase) and reflects total mast cell number + mast cell degranulation (assay for mature beta tryptase reflecting pure mast cell degranulation is not available clinically)



Treatment




References