2023 BONUS E-LECTURE:

Allergy & Clinical Immunology

With Contributions by Dr. Andrea Burke and Dr. David Fahmy
Clinical Immunology & Allergy
Primary Immunodeficiency (PID)

Ten Red Flags of Immunodeficiency:

1. ≥ 2 new ear infections within 1 year
2. ≥ 2 new sinus infections within 1 year, in the absence of
allergy
3. One pneumonia per year for more than 1 year
4. Chronic diarrhea with weight loss
5. Recurrent viral infections (colds, herpes, warts, condyloma)
6. Recurrent need for IV antibiotics to clear infections
7. Recurrent, deep abscesses of the skin or internal organs
8. Persistent thrush or fungal infection on skin or elsewhere
9. Infection with normally harmless tuberculosis-like bacteria
10. A family history of Primary Immunodeficiency

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 Primary Immunodeficiency (PID)
General Approach:
• Rule out secondary causes of immunodeficiency:
– DM, HIV infection, Cirrhosis, Nephrotic syndrome, Autoimmune disease, Malignancy,
Splenectomy/Asplenia, Immunomodulatory drugs
– Structural (obstructive tumours, urethral strictures), dermatitis, burns
• Identify type of infections (see below) to direct investigation
PREDOMINANT INFECTIONS TYPE OF IMMUNO- Investigations
DEFICIENCY
Repeated pyogenic infections B- cell Lymphocyte count, Lymphocyte subsets,
Immunoglobulins (IgG, IgA, IgM),
vaccination titres
Severe mycotic infection and T- cell Lymphocyte count, Lymphocyte subsets
opportunistic infections
Abscess-forming infection with Neutrophil deficiency Neutrophil count, Chronic Granulomatous
low-grade pathogens Disease (CGD) Assay
Repeated infections w/ Complement C3, C4, CH50
Neisseria sp. deficiency
 Immunodeficiency to know: CVID
Combined Variable Immunodeficiency (CVID)
• Most common symptomatic PID in adults
– Recurrent sinopulmonary infections
– Dx: LOW IgG + LOW IgA or IgM + poor response to vaccination;
other immunodeficiency causes ruled out (e.g. CLL)
– Tx: IVIG or SCIG (sub-cutaneous Immunoglobulin)

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 Urticaria (1)
Acute Urticaria
• Common antigens/triggers = antibiotics (PCN, Sulfa), NSAIDs, insects, food
(shellfish in adults) - if there’s a trigger, there will be an obvious relationship
• Lasts < 6 weeks
• Work-up: Allergy referral for skin testing
• First line treatment: STOP medication/AVOID trigger if identified, anti-
histamines PRN: ex. Cetirizine (Reactine)

Red Flags of Urticaria: Typical Urticaria:

Last longer than 48hr Last <48hr
Heal with a bruise, scar Heal without skin changes
Burning, pain PRURITUS!
PEARL: Red Flags should raise suspicion of autoimmune/
systemic disease!!!
 Urticaria (2)
Chronic Spontaneous Urticaria (CSU)
• “Chronic”: >6 weeks, most days of the week, “Spontaneous”: no clear trigger
• Workup of CSU
– CBC + diff, ESR/CRP
• Workup of other causes of chronic urticaria – as directed by clinical picture:
– Autoimmune work-up: ANA, ds-DNA, RF
– Serum tryptase if systemic symptoms [Mastocytosis]
– Biopsy [urticarial vasculitis]
• Treatment of CSU
– 1st line: Daily non-sedating antihistamine (cetirizine)
– 2nd line: increased dose non-sedating antihistamine (4x
– 3rd line: Omalizumab (Xolair)
Physical Chronic Urticaria
• Trigger = Pressure (aka dermatographism), Heat, Cold
 Angioedema
Angioedema + pruritus/urticaria = most likely Mast cell mediated Acute Treatment Angioedema:
• Related to a Specific Trigger (food, drug, insect bite, etc.) STOP offending agent/trigger, if possible
• Idiopathic Angioedema (can be part of CSU) H1-Blocker: Diphenhydramine 25-50mg IV
H2-Blocker: Ranitidine 50mg IV
Angioedema (NO pruritus/urticaria) = Mast cell OR Bradykinin-mediated
Steroids: Methylprednisolone ~60-80mg IV
• Differential diagnosis: *Anaphylaxis or oropharyngeal angioedema: Epi!
– Related to Specific Trigger (see above) ACE Inhibitor Angioedema: Icatibant
– Idiopathic Angioedema Known HAE: skip above treatment, instead: C1
• Chronic Tx: Frequent episodes : Daily antihistamine (Cetirizine) esterase inhibitor, Icatibant
• Rare episodes: Prednisone + antihistamine for first sign of symptoms Investigations:

• Epinephrine Auto-injector Type C1 Inhibitor C1 Inhibitor C4

Level Function
– Hereditary Angioedema (HAE): C1 esterase inhibitor deficiency – Types I, II, III HAE Type I Low Low Low

• PEARL: in general, a normal C4 level (in acute setting) rules OUT HAE Type II Normal/High Low Low

HAE Types I &II HAE Type III Normal Normal Normal

• Chronic Tx: Prophylactic C1 esterase Inhibitor Acquired Low Low Low

– Acquired Angioedema (lymphoproliferative or autoimmune disease) ACE In Normal Normal Normal

– ACE Inhibitor Angioedema Idiopathic Normal Normal Normal

NEW: NEJM 2015: A Randomized Trial of Icatibant in ACE-Inhibitor–Induced Angioedema

Conclusion: in this RCT involving patients with ACE-inhibitor–induced angioedema, complete resolution of edema was achieved
significantly more quickly with SQ icatibant than with standard therapy consisting of glucocorticoids and antihistamines.
 Anaphylaxis
• Common Triggers: food, medication, latex, insect venom
• Diagnosis: see next slide
• Acute Treatment IM EPINEPHRINE
– ABCs, MOIF 0.01 mg/kg (max 0.5mg) IM
Repeat q5-15 min PRN
– STOP drug/REMOVE trigger (if identified) Note: 1:1000 solution = 1mg/mL
– Epinephrine IM: 1:1000 (1mg/mL) – DOSE: 0.01mg/kg (max 0.5mg)
IM in anterolateral thigh, repeat q5-15min IV EPINEPHRINE
0.05-0.1 mg IV over 5 min
– Epinephrine IV: 1:10,000 (0.1mg/mL) – BOLUS: 0.05-0.1 mg IV over 5 Then infuse 2-10 mcg/min titrated
min, then INFUSE: 2-10mcg/mL to BP
• Consider IV after several (i.e. 3) doses IM, profound hypotension, obese Note: 1:10,000 solution =
patients 0.1mg/mL
• Adjunctive medications:
– H1-Blocker: Ranitidine 50mg IV q8hr PRN
– H2-Blocker: Diphenhydramine 25-50mg IV q4-6hr PRN
– Steroids: Methylprednisolone 125mg IV q6hr PRN Discharge Plan:
Prescribe Epinephrine Autoinjector 0.3mg
– Glucagon – patients on beta-blockers IM PRN
– Salbutamol – patients with signs of bronchoconstriction Anaphylaxis Action Plan
– Vasopressors – for persisting hypotension Patient/Caregiver Education
• Observe until symptoms improving, min. 4-6hr MedicAlert bracelet
Referral to Allergist/Immunologist
ANAPHYLAXIS: Clinical Criteria for diagnosis Kim & Fischer AACI 2011, 7(Suppl 1):S6
Anaphylaxis is highly likely when ANY ONE of the following 3 criteria is fulfilled following exposure to an allergen:
1. Acute onset of an illness (min to several hours) with
q Skin or mucosal tissue involvement (or both)
• Generalized hives, itch/flushing, swelling of lips/tongue/uvula ANAPHYLAXIS =
AND at least ONE of the following: one of:
q Respiratory compromise 1. Possible
• Dyspnoea, wheeze, bronchospasm, stridor, reduced PEF, hypoxemia allergen +
q Hypotension or associated symptoms of end-organ dysfunction Skin/mucosa
• Hypotonia, syncope, incontinence + ≥ 1 of
Resp
2. TWO or more of the following that occur rapidly (min to several hours) after exposure to a likely allergen for HoTN/EOF
that patient
q Skin or mucosal tissue involvement 2. Likely Allergen +
• Generalized hives, itch/flushing, swelling of lips/tongue/uvula ≥ 2 of
q Respiratory compromise Skin/mucosa
• Dyspnoea, wheeze, bronchospasm, stridor, reduced PEF, hypoxemia Resp
HoTN/EOF
q Hypotension or associated symptoms of end-organ dysfunction GI
• Hypotonia, syncope, incontinence
q Persistent GI symptoms 3. Known
• Painful abdominal cramps, vomiting Allergen +
3. Hypotension after exposure to a known allergen for that patient (min to several hours) HoTN
q Adults: sBP <90 mmHg or >30% decrease from patient’s baseline

PEARL: As a general rule, any time you have more than one system involved, you should suspect anaphylaxis!
 Penicillin Allergy
Approach:
– IgE-Mediated: pruritus, urticaria, angioedema, etc.
– Non-IgE-Mediated: SJS-TENS (blistering, desquamation, conjunctivitis), DRESS (eosinophilia, fever, end-organ
involvement), serum sickness (arthritis, fever)
Management: IgE-mediated Reactions
– Allergy referral for Penicillin Skin Testing + Oral Challenge
• ~90% “PCN allergic” patients will test negative – can safely receive beta-lactam and cephalosporin antibiotics
• Positive skin test – AVOID penicillin, higher likelihood of reacting to 1st gen cephalosporins
– Drug Desensitization (under close observation, OK to do even in Pregnant patient (eg) with syphilis))
• If penicillin is required acutely and no time for skin testing, or skin test positive
• Note: this is a temporary induction of ‘tolerance’, and does NOT rule out allergy
• Note: this is only used in cases of IgE-mediated drug reactions (NOT if any suspicion of serum sickness, SJS-TENS,
DRESS, etc.)
– Note: Aztreonam (monobactam) – generally tolerated in penicillin allergic patients
• exception: if they have reacted to ceftazidime!
Patient history not very reliable (JAMA 2001):
PCN allergy history positive: LR+ 1.9 for +ve skin test
PCN allergy history negative: LR- 0.5 for +ve skin test
 Example Question
A 30-year-old woman presents with a second pneumonia in the last
six months. She has a past medical history of recurrent pneumonias
and sinusitis. Investigations show: WBC 6, Neutrophils 3,
Lymphocytes 2, Monocytes 1.
What is most likely diagnosis?
1. Complement deficiency
2. Common variable immunodeficiency
3. HIV
4. Chronic granulomatous disease
 Answer
A 30-year-old woman presents with a second pneumonia in the last
six months. She has a past medical history of recurrent pneumonias
and sinusitis. Investigations show: WBC 6, Neutrophils 3,
Lymphocytes 2, Monocytes 1.
What is most likely diagnosis?
1. Complement deficiency
2. Common variable immunodeficiency
3. HIV
4. Chronic granulomatous disease
 Example Question
A middle-aged female presents with a 6 month history of urticaria. She
has never had any episodes of swelling. The urticaria resolve within 12hr,
with no residual bruising or scarring. She reports that she has been eating
out at restaurants more recently. She is otherwise well. Initial bloodwork
is normal including a CBC, creatinine and liver profile. What is the most
likely cause of this patient’s symptoms?
1. Chronic Idiopathic Urticaria
2. Food allergy
3. C1 esterase deficiency
4. Autoimmune Disease
 Answer
A middle-aged female presents with a 6 month history of urticaria. She
has never had any episodes of swelling. The urticaria resolve within 12hr,
with no residual bruising or scarring. She reports that she has been eating
out at restaurants more recently. She is otherwise well. Initial bloodwork
is normal including a CBC, creatinine and liver profile. What is the most
likely cause of this patient’s symptoms?
1. Chronic Idiopathic Urticaria
2. Food allergy
3. C1 esterase deficiency
4. Autoimmune Disease
 Example Question
A pregnant patient with a history of asthma states she is allergic to
penicillin. She developed wheeze the last time she took it, while
admitted for an upper respiratory tract infection. She was referred
for penicillin skin testing, which was negative.
Penicillin is now indicated for a pregnancy acquired syphilis infection.
Which drug would you use?
1. Penicillin
2. Second-Generation Cephalosporin
3. Doxycycline
 Answer
A pregnant patient with a history of asthma states she is allergic to
penicillin. She developed wheeze the last time she took it, while
admitted for an upper respiratory tract infection. She was referred
for penicillin skin testing, which was negative.
Penicillin is now indicated for a pregnancy acquired syphilis infection.
Which drug would you use?
1. Penicillin
2. Second-Generation Cephalosporin
3. Doxycycline
 Example Question
A young man presents with occasional angioedema of his lips and
hands. Which of the following features make it least consistent with
C1 esterase deficiency?
1. Occasional GI symptoms
2. Triggered by dental procedure
3. Presence of urticaria
4. Laryngeal involvement
 Answer
A young man presents with occasional angioedema of his lips and
hands. Which of the following features make it least consistent with
C1 esterase deficiency?
1. Occasional GI symptoms
2. Triggered by dental procedure
3. Presence of urticaria
4. Laryngeal involvement