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172 Textbook of Diagnostic and Therapeutic Procedures in Allergy
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Table 8. Example of Intravenous Penicillin Desensitization Protocol.
Dose
Number
1 0.01 6 0.015 0.015
2 0.01 12 0.03 0.045
3 0.01 24 0.06 0.105
4 0.01 50 0.125 0.23
5 0.1 10 0.25 0.48
6 0.1 20 0.5 1.0
7 0.1 40 1.0 2.0
8 0.1 80 2.0 4.0
9 0.1 160 4.0 8.0
10 10.0 3 7.5 15.0
11 10.0 6 15.0 30.0
12 10.0 12 30.0 60.0
13 10.0 25 62.5 123.0
14 10.0 50 125.0 250.0
15 10.0 100 250.0 500.0
16 10.0 200 500.0 1000.0
The time interval between doses should be 15 minutes, and it should 30 minutes before the nal dose. Approximate
duration of the whole procedure is 4.5 hours. Reproduced with permission from de Groot, H., W. M. Mulder and I.
Terreehorst. 2012. Utility of desensitisation for allergy to antibiotics. Neth J. Med. 70(2): 58–62.
Penicillin
Concentration
(mg/mL)
Infusion
Rate
(mL/h)
Dose
(mg)
Cumulative
Dose (mg)
Time Heart
Rate
Blood
Pressure
Respiratory
Rate
Oxygen
Saturation
2. A 32-year-old female patient had anaphylaxis during an appendectomy. The acute serum
tryptase level was 45 ng/L at 30 minutes post-anaphylaxis and a baseline measurement at
24 hours was 30 ng/L. The patient received atracurium, fentanyl, propofol and ondansetron
at induction. Skin test (intradermal) confirmed a positive reaction to atracurium, and
there was no demonstrable sensitization to fentanyl, propofol, ondansetron, latex and
chlorhexidine. Tests were also undertaken for rocuronium and suxamethonium as
alternative NMBAs and these were negative. What is the most appropriate approach?
This young patient developed anaphylaxis during the procedure, and baseline serum tryptase
level was persistently high suggestive of a possible clonal mast cell disorder such as systemic
mastocytosis. The key step in long-term management is to avoid certain triggers as far as
possible than can induce mast cell activation and these include:
1. Pharmacological agents with histamine-releasing properties: radio-contrast medium (RCM),
opiates, NMBAs (especially atracurium and mivacurium), vancomycin, amphotericin B and
NSAIDs. These drugs are not contraindicated if there is no previous history of an allergic
reaction or if the patient has shown clinical tolerance recently. However, it is recommended
that the first dose is administered under close clinical supervision with immediate access to the
management of anaphylaxis in a hospital setting. Some clinicians prefer to premedicate patients
with high-dose antihistamines and/or corticosteroids prior to administration of RCM.
2. Mechanical factors include tourniquet pressure and trauma.
3. Sudden change in temperature; a cold operating room or cold intravenous fluid.
4. Bee and wasp stings.
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It is important to be aware of the pharmacological effect of the drugs that are routinely used
during the induction or maintenance of anesthesia. A physiological drop in blood pressure after
induction can occur because of the vasodilator effect of these agents. Also, reactions related to
transfused blood products or colloids, and hypotension or hypoxia secondary to other medical
problems (acute myocardial infarction and pulmonary embolism), should not be confused with
allergic reactions
When evaluating a patient with a history of perioperative anaphylaxis, it is useful to perform
skin testing for the drugs used during the procedure as well as for safe alternatives to consider in the
future. In addition, latex, antiseptics, and diagnostic dyes should be included in the evaluation of
any perioperative reactions. Because of the intrinsic histamine-releasing activity of neuromuscular
blocking agents, it is recommended to use two dilutions for skin prick testing to minimize the risk
of false positive results. These are the neat concentration and the 1:10 dilution for skin prick testing.
The risk of a false-positive is even greater with intradermal testing, therefore further dilution is
needed. A general approach to patients with perioperative reactions is summarized in Flowchart 2
(Garvey et al. 2019; Ewan et al. 2009).
3. A 53-year-old male patient presented with acute myocardial infarction, and he is planned to
receive dual antiplatelets for percutaneous coronary intervention. He has well-controlled
asthma and has undergone two operations for nasal polyps. There is documented history
of “aspirin allergy”—reports wheezing and a possible throat swelling 30 minutes after the
first dose about 5 years ago. What is the most appropriate approach?
Aspirin is a nonsteroidal anti-inflammatory drug (NSAID). Several phenotypes have been
identified for NSAID reactions. This includes:
• Aspirin exacerbated respiratory disease (AERD); as in this patient
• NSAID-exacerbated cutaneous disease (NECD)
• NSAID-induced urticaria and/or angioedema (NIUA) in chronic spontaneous urticaria
• Single NSAID-induced urticaria/anaphylaxis
Aspirin desensitization is indicated for this patient. Successful desensitization protocols have
been reported in patients with acute ischemia. Aspirin desensitization is usually done over a few
hours, but the protocol can be customized to be over a day or two. An example of a protocol that is
adopted in our center (Heartlands Hospital) is shown in Table 9. If the patient develops any allergy
symptoms, treat the reaction promptly and go back 2–3 steps in the protocol prior to cautiously
repeating the dose that induced the reaction.
4. A 43-year-old male with no previous medical illness has been admitted with community-
acquired pneumonia. The medical team wants to commence amoxicillin, but he has a
penicillin allergy label on his record. The patient reports a very mild rash (not urticaria
and nothing to suggest vasculitis, desquamation, mucosal or systemic involvement) on
day 4 of treatment with amoxicillin for a urinary tract infection 10 years ago. What
management options can you provide for this patient?
Clinical presentation is not suggestive of an immune-mediated reaction (i.e., ‘low risk’ as
described in the previous section). This patient is suitable for a “direct oral penicillin challenge”
without undertaking allergy tests. He should be counseled, written informed consent obtained
and 500 mg amoxicillin can be administered orally and the patient monitored for an immediate
allergic reaction. If Type-1 HSRs are excluded, a full therapeutic dose of amoxicillin is
administered, and the patient is monitored for non-immediate HSRs. After the patient confirms
clinical tolerance to the therapeutic course, the penicillin allergy label can be removed from his
records, and written communication is provided to the patient’s family physician. This process
is called penicillin allergy de-labeling.
174 Textbook of Diagnostic and Therapeutic Procedures in Allergy
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Flowchart 2. A general approach to patients with perioperative reactions.
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Table 9. A suggested protocol for aspirin desensitization.
Time (min) Aspirin Dose (mg) Volume (ml)
0
30
60
90
210
330
1
5
10
20
40
100
If, on the other hand, the patient reported symptoms suggestive of an immediate or non-
immediate HSRs (urticarial, angioedema, wheeze, etc.), the patient is stratified as “high risk,”
i.e., not suitable for a direct oral penicillin challenge, the current infection is managed with an
alternative antibiotic and penicillin allergy de-labeling may be considered electively and this
would involve skin tests ± DPT as described in previous sections. Please look at Flowchart 3.
5. You have received a consultation from the medical ward, regarding a 58-year-old male
patient who has just been admitted with pyelonephritis, and the team would like to start
ceftriaxone for him. The patient has a penicillin allergy label, and the team is wondering
about the safety of introducing cephalosporin to this patient.
Penicillin and cephalosporin cross-reactivity exists in the context of Type-1 HSRs. The estimated
percentage of penicillin-allergic patients that react upon introducing cephalosporin varies in
the literature from 0.2% to 8%. Cross-reactivity is expected to be more if the penicillin and
cephalosporins share a side chain. These could include amoxicillin and cefadroxil or ampicillin
and cephalexin. When considering cephalosporins in a patient with penicillin allergy, consider
the approach illustrated in Flowcharts 3 and 4.
Glossary of Abbreviations
AGEP – Acute Generalized Exanthematous Pustulosis
BP – Blood Pressure
EBV – Epstein-Barr Virus
DPT – Direct Provocation Tests
DRESS – Drug Rash With Eosinophilia and Systemic Symptoms
GDP – Glucose-6-Phosphate Dehydrogenase
HR – Heart Rate
HSR – Hypersensitivity Reaction
MRGPRX2 – Mas-Related G-Protein-Coupled Receptor X2
NMBA – Neuromuscular Blocking Agents
PEFR – Peak Expiratory Flow Rate
P-I – Pharmacological Interaction With Immune Receptors
SJS – Stevens-Johnson Syndrome
SSIgE – Serum-Specific Immunoglobulin E
TEN – Toxic Epidermal Necrolysis
e to consent or give a
• Based on family history of PenA
FLOWCHART 4. Introducing cephalosporins to patients with penicillin allergy.
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176 Textbook of Diagnostic and Therapeutic Procedures in Allergy
gy specialist.gy by non-allerA practical approach to penicillin allerFlowchart 3.
• Benign rash only
• Pruritis only
• Non-specific symptoms only (eg: GIT symptoms, headache, dizziness, etc)
• History >10years ago with no features of IgE mediated reaction
* Switch to ‘high risk’ algorithm for type-1 HSR in pregnancy, clinically unstable or severe cardio-respiratory compromise, unabl
reliable history until patient is de-labelled by allergist
@ Contraindicated if index reaction is suggestive of Severe Cutaneous Adverse Reactions (SCAR)
# Referral to allergy specialist must be considered at a later time point
**CRITERIA:
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Flowchart 4. Introducing cephalosporins to patients with penicillin allergy.
178 Textbook of Diagnostic and Therapeutic Procedures in Allergy
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References
Brockow, K., Garvey, L. H., Aberer, W., Atanaskovic-Markovic, M., Barbaud, A., Bilo, M. B., Bircher, A. et al. 2013.
Skin test concentrations for systemically administered drugs—an ENDA/EAACI Drug Allergy Interest Group
position paper. Allergy 68(6): 702–712.
Broyles, A. D., Banerji, A., Barmettler, S., Biggs, C. M., Blumenthal, K., Brennan, P. J. et al. 2020. Practical guidance
for the evaluation and management of drug hypersensitivity: specific drugs. J. Allergy Clin. Immunol. Pract.
8(9S): S16–S116.
De Groot, H., Mulder, W. M. and Terreehorst, I. 2012. Utility of desensitisation for allergy to antibiotics. Neth J. Med.
2012 Mar; 70(2): 58–62.
Demoly, P., Adkinson, N. F., Brockow, K., Castells, M., Chiriac, A. M., Greenberger, P. A. et al. 2014. International
Consensus on drug allergy. Allergy 69(4): 420–437.
Ewan, P. W., Dugué, P., Mirakian, R., Dixon, T. A., Harper, J. N., Nasser, S. M. et al. 2010. BSACI guidelines for the
investigation of suspected anaphylaxis during general anaesthesia. Clin. Exp .Allergy 40(1): 15–31.
Garvey, L. H., Ebo, D. G., Mertes, P. M., Dewachter, P., Garcez, T., Kopac, P. et al. 2019. An EAACI position paper
on the investigation of perioperative immediate hypersensitivity reactions. Allergy 74(10): 1872–1884.
Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College
of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: An
updated practice parameter. Ann. Allergy Asthma Immunol. 105(4): 259–273.
Krishna, M. T. and Huissoon, A. P. 2011. Clinical immunology review series: an approach to desensitization. Clin.
Exp. Immunol. 163(2): 131–146.
Lee, C. E., Zembower, T. R., Fotis, M. A., Postelnick, M. J., Greenberger, P. A., Peterson, L. R. et al. 2000. The
incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and
emerging bacterial resistance. Arch. Intern. Med. 160(18): 2819–2822.
Macy, E. and Contreras, R. 2014. Health care use and serious infection prevalence associated with penicillin “allergy”
in hospitalized patients: A cohort study. J. Allergy Clin. Immunol. 133(3): 790–796.
Mirakian, R., Ewan, P. W., Durham, S. R., Youlten, L. J., Dugué, P., Friedmann, P. S. et al. 2009. BSACI guidelines
for the management of drug allergy. Clin. Exp. Allergy 39(1): 43–61.
Mirakian, R., Leech, S. C., Krishna, M. T., Richter, A. G., Huber, P. A., Farooque, S. et al. 2015. Management of
allergy to penicillins and other beta-lactams. Clin. Exp. Allergy 45(2): 300–327.
NICE. 2014. The National Institute for Health and Care Excellence. Drug Allergy: Diagnosis and Management.
pp. 5–6.
Pichler, W. J. 2019. Immune pathomechanism and classification of drug hypersensitivity. Allergy 74(8): 1457–1471.
Romano, A., Atanaskovic-Markovic, M., Barbaud, A., Bircher, A. J., Brockow, K., Caubet, J. C. et al. 2020.
Towards a more precise diagnosis of hypersensitivity to beta-lactams—an EAACI position paper. Allergy
75(6): 1300–1315.
Scherer, K., Brockow, K., Aberer, W., Gooi, J. H., Demoly, P., Romano, A. et al. 2013. Desensitization in delayed
drug hypersensitivity reactions—an EAACI position paper of the Drug Allergy Interest Group. Allergy
68(7): 844–852.
Thong, B. Y. and Tan, T. C. 2011. Epidemiology and risk factors for drug allergy. Br J. Clin. Pharmacol.
71(5): 684–700.
West, R. M., Smith, C. J., Pavitt, S. H., Butler, C. C., Howard, P., Bates, C. et al. 2019. ‘Warning: Allergic to
penicillin’: association between penicillin allergy status in 2.3 million NHS general practice electronic health
records, antibiotic prescribing and health outcomes. J. Antimicrob. Chemother, 74(7): 2075–2082.
Chapter 8
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Laboratory Analysis of Primary
Immunodeficiency
Vijaya Knight1 and Mandakolathur R. Murali2,*
Introduction
Immunodeficiency is defined as the inability to produce an adequate immune response due
to the partial or complete absence of a component of the immune system or it can be caused by
functional deficits in one or more components of the immune system. Immunodeficiency generally
manifests as increased susceptibility to infection; however, autoimmunity (Schmidt et al. 2017),
inflammation (Fodil et al. 2016), allergy (Chan and Gelfand 2015) and malignancy (Pai et al. 2021)
are increasingly being recognized as possible initial clinical presentations of immunodeficiency.
These clinical presentations may occur at any stage of life, from infancy to adulthood. Therefore,
immunodeficiency should have a differential diagnosis when evaluating patients with recurrent,
treatment-refractory or unusual infections, autoimmunity, unexplained lymphadenopathy and
allergies including food allergies. Immunodeficiency may either be inherited [otherwise known as
“Inborn Errors of Immunity (IEI)” or Primary Immunodeficiency (PID)] or acquired due to extrinsic
factors (Secondary Immunodeficiency or SID). The causes of secondary immunodeficiency are
listed in Table 1.
Inherited immunodeficiency (IEI) is due to pathogenic, germline variants in genes that are responsible
for immune development and/or function. To date, 406 distinct IEIs with 430 different gene defects
have been identified (Bousfiha et al. 2020). IEI can be autosomal or X-linked with dominant or
recessive inheritance patterns. Furthermore, the gene defect may be fully or partially penetrant,
leading to severe or milder clinical presentations, respectively. The clinical presentation of IEI
is highly variable and includes increased susceptibility to infection, autoimmune manifestations,
malignancy and/or inflammatory conditions. Other features include failure to thrive, diarrhea
1
Associate Professor, University of Colorado School of Medicine, Department of Pediatrics, Section of Allergy and
Immunology, Children’s Hospital, Colorado, Translational and Diagnostic Immunology Laboratory, 13123 East 16th
Avenue, Aurora, Colorado 80045.
2
Director of Clinical Immunology laboratory, Departments of Medicine and Pathology, Massachusetts General Hospital,
Assistant Professor of Medicine, Harvard University, Boston, Massachusetts 02114.
Email: vijaya.knight@childrenscolorado.org
* Corresponding author: murali50@aol.com
Inborn Errors of Immunity (IEI)
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Table 1. Causes of secondary immunodeficiency.
Cause Description References
Infection HIV infection is well recognized as a cause of secondary
immunodeciency, leading to the gradual destruction of CD4+ T
lymphocytes and extreme susceptibility to opportunistic organisms.
Infection with several other pathogens can lead to immunodeciency,
including measles, inuenza, HTLV, malaria and Bordetella.
Immunodeciency in some of these cases may be transient
Malnutrition The most common cause of secondary immunodeciency, worldwide.
A deciency of micronutrients required for adequate development
of the innate and adaptive immune system results in diminished and
inadequate immune response and oftentimes a quantitative decrease in
immunoglobulins and lymphocyte subsets
Chemotherapy/
Immunosuppressive
– Therapy
Extremes of Age Neonates are particularly susceptible to infection owing to the immaturity
Surgery and Trauma May be accompanied by post-surgical or trauma-related
Metabolic Diseases Diabetes mellitus and uremia have deleterious eects on immunity, leading
Environment Exposure to ionizing radiation, ultraviolet light, chronic cold or heat
Chemotherapy leads to bone marrow suppression biologics, such as
rituximab selectively deplete lymphocyte populations, and pathway
inhibitors such as JAK inhibitors suppress immune activation. Radiation
therapy impairs innate and adaptive immunity
of their immune system and lack of antigenic exposure
Older individuals are at a higher risk of infections and malignancy owing
to the diminished ability of the immune response to mount an adequate
response to foreign antigens
immunosuppression
to compromised innate and adaptive immune responses
exposure can have adverse eects on the immune system
(Chinen and
Shearer 2010)
(Bourke et al.
2016)
(Henrickson et al.
2016)
(Goronzy 2019)
(Moins-Teisserenc
et al. 2021)
(Berbudi et al.
2020; Steiger et al.
2022)
(Lumniczky et al.
2021)
Table 2.
The current IUIS classification of IEI.
Category Examples
Immunodeciencies aecting
cellular and humoral immunity
Combined Immunodeciency
(CID) with Associated Syndromic
Features
Predominantly Antibody Defects X-linked agammaglobulinemia and common variable immunodeciency
Disease of Immune Dysregulation Familial hemophagocytic lymphohistiocytosis, Chediak-Higashi syndrome,
Congenital Defects of Phagocyte
Number/Function
Innate Immune Defects Mendelian susceptibility to mycobacterial disease (IFNγ and IL-12 Pathway
Auto-inammatory defects Inammasome-associated auto-inammatory syndromes, such as familial
Complement Defects Deciencies in individual complement pathway proteins and Hereditary
Bone marrow failure Fanconi anemia and Dyskeratosis congenita
Phenocopies of IEI Atypical hemolytic uremic syndrome (aHUS), pulmonary alveolar proteinosis (PAP)
Severe combined immunodeciency (SCID), CD40 ligand deciency and bare
lymphocyte syndrome 1 and 2
DiGeorge syndrome, Wiskott Aldrich syndrome, ataxia and telangiectasia
autoimmune lymphoproliferative syndrome, immune dysregulation,
polyendocrinopathy, enteropathy and X-linked syndrome (IPEX), autoimmune
polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED)
Shwachman-Diamond syndrome, chronic granulomatous disease (CGD), leukocyte
adhesion deciency (LAD) I, II and III
Defects)
Mediterranean fever (FMF), Muckle-Wells syndrome, etc., and Type 1
Interferonopathies
Angioedema (HAE)
and adult-onset immunodeciency with susceptibility to mycobacterial disease
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and generalized skin lesions. The International Union of Immunological Societies (IUIS) expert
committee on IEI reviews and proposes the classification of IEI every other year, organizing the
information into the phenotypic classification of IEI and their associated gene defects. The latest
reviews of well-characterized IEIs define ten distinct categories, as shown in Table 2 (Bousfiha et al.
2020; Tangye et al. 2022). A few examples of immune disorders are provided under each category.
Infectious Presentations of IEI
Although the clinical presentation of IEI can be varied, when the infection is the chief clinical
complaint, knowledge of the association of certain infectious presentations with specific immune
defects may guide the investigation of the immune system. Loss of or compromised function
of specific immune cell populations can increase susceptibility to specific groups of pathogens.
Therefore, in addition to the IUIS classification of IEI, laboratory workup for IEI may be guided
by the infectious presentation. Phenotypically, IEI can be broadly classified into defects affecting
T cells, B cells, neutrophils and other innate immune cells, such as monocyte/macrophages and the
complement pathway (Table 3).
Table 3. Association of specific immune component with infectious presentation.
Defective Immune
Component
T Cell Defects
B Cell Defects
Neutrophil Defects
Innate immune
defects (monocyte/
macrophage)
Complement
Defects
Infectious Presentation/Associated Specific Pathogens
• Systemic or organ-specific bacterial, fungal, viral or opportunistic pathogen infections.
• Severe infections that may be treatment refractory.
• Pathogens include Pneumocystis jirovecii, Candida albicans, Cryptococcus neoformans,
cytomegalovirus, rotavirus, mycobacteria, including atypical mycobacterial species and BCG
vaccine, and live viral vaccine strains, such as measles vaccine.
• Repeated respiratory tract infections, such as sinusitis and pneumonia.
• Common pathogens include encapsulated bacteria, such as Streptococcus pneumoniae,
Haemophilus influenzae, Neisseria and meningitidis.
• Gastrointestinal infections with Giardia lamblia.
• Deep-seated skin or organ infections.
• Poor wound healing.
• Common pathogens include Staphylococcus aureus, gram-negative bacteria, Candida albicans,
and Aspergillus species.
• Intracellular infections may be localized to an organ or may be disseminated.
• Common pathogens include Mycobacterium tuberculosis, and non-tuberculous mycobacteria,
such as Mycobacterium avium, Salmonella species and Varicella-Zoster virus.
• Sinusitis, pneumonia and meningitis
• Autoimmune diseases
• Capsulated organisms, such as Streptococcus pneumoniae and Neisseria meningitidis.
Neisserial meningitis is almost exclusively seen in defects of the alternative and terminal
complement pathways
T Cell Deficiency
Patients with T cell defects present with a broad range of non-infectious and infectious presentations
and are typically susceptible to infection with opportunistic pathogens such as Pneumocystis
jiroveci and atypical mycobacteria. However, they also suffer serious infections with common viral
pathogens (e.g., cytomegalovirus, adenovirus, viral vaccine strains), bacteria and fungi. Because T
cell help is required for robust antibody production, these patients also suffer from compromised
humoral immunity and may have antibody production deficits and compromised ability to mount
an effect antibody response following vaccination or infection. Thus, T cell defects are most often
accompanied by some form of depressed B cell immunity and are generally referred to as “Combined
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