macro

Adults: 1.Two or more ear infections / year 2.Two or more sinus infections/ year (in absence of allergy) 3.One pneumonia per year for more than one year (must be CXR documented) 4.Chronic diarrhea + weight loss 5.Recurrent viral infections (colds, herpes, warts, condyloma) 6.Recurrent need for IV antibiotics to clear infection. 7.Long duration or multiple courses of antibiotics 8.Recurrent deep abscesses of skin / internal organs 9.Persistent thrush/ fungal skin infections 10.Infected with normally harmless TB- like bacteria. ** if you have positive history of infection, ask in detail (age of onset, circumstance, type of bug, where they vaccinated for this bug, how long did it need to be cleared, complications)

Warning Signs of PIDDs in Children

1. ≥4 new ear infections within 1 year
2. ≥2 serious sinus infections within 1 year
3. ≥2 months on antibiotics with little effect
4. ≥2 pneumonias within 1 year
5. Failure of an infant to gain weight or grow normally 6. Recurrent, deep skin or organ abscesses
6. Persistent thrush in mouth or fungal infection of skin 8. Need for IV antibiotics to clear infections
7. ≥2 deep-seated infections, including septicemia
8. A family history of PIDD

Autoimmune review of systems – rash, photosensitivity, ulcers, Reynaud’s, arthritis/arthralgia, sicca symptoms, abdominal pain, neuropathy/focal weakness • Cancer Constitutional symptoms and age-appropriate cancer screening developmental issues fhx: autoimmune, immune def, infections, relative died young unknown, cancer

AP:

=> We have ordered quantitative Igs (IgG, IgM, IgA) as well as a response assay to vaccination (tet and dip for protein, pneumococcal for polysacc). Can consider flow cytometry for B, T, NK cells, C3/C4, CBC, HIV testing, CH50 (completment), neutrophil burst assay => Immunoglobulin replacement is the mainstay of preventative therapy of recurrent infections.

• IVIG > 400 to 600 mg/kg every three to four weeks vs:
• SCIG (more stable IgG numbers, good for people who react to IVIG, poor IV access, self administered at home, improved QoL) Higher doses may be required in patients with bronchiectasis and in those with protein-losing enteropathy Calculation for weight appropriate dose of IG: https://ivig.transfusionontario.org/dose The half-life of IG is approximately 30 days, Steady-state levels are usually achieved after three to six months of therapy => followup and screening: Pulmonary function testing yearly, CT thorax q5y, serum b12/iron qyear => IVIG monitoring? CBC, lytes, renal, ALT, quant Ig trough levels? => avoid live vaccinations such as live shingles, live flu shot, etc

from talk 07/02/2025

Categorization: primary vs secondary, innate vs adaptive, T cell vs B cell

Some terms:

• PIDD (primary immune deficiency disease)
• IEI (inborn errors of immunity)

older terms are PID (primary immune deficiency) but this is now outdated. IEI is an umbrella term covering PIDD, autoimmune diseases, allergies... etc

Epidemiology quick facts (no sources for this attached):

• Secondary >>common than PIDD.
  • Malnutrition, HIV, malignancy, drugs, protein loss (ie nephrotic syndrome), metabolic disease (ie. diabetes, liver disease)

  so for that reason when ordering quant Igs it is helpful to order serum albumin too

  • drug related, atopic eczema and breakdown of skin barrier, PCD, seasonal allergies, heart disease, CF, asthma ...
• for PIDD
  • 1 in 500 including milder forms
  • 1 in 1200 serious PIDD

An aside:

PIDD is heavily associated with autoimmune disorders. Why? It has to do with normal physiology; our immunoogical equilibrium examples: most commonly autoimmune cytopenias; others include bronchiectasis, in 20% of CVID autoimmune disease precedes infections

Below is primarily for primary IEI

Suggestive history: (fellows should memorize criteria)

• = 2 new ear infections in 1y
• = 2 new sinus infections within 1y in absence of allergy
• one pna per year for >1y
• chronic diarrhea with weight loss
• recurrent viral infections (colds, herpes, warts, condyloma)
• Recurrent need for IV antibiotics
• Recurrent deep abscesses of the skin or internal organs
• persistent thrush or fungal infection, skin or elsewhere
• infection with normally harmless NTM
• family history of PIDD

HOWEVER: these 10 warning signs are NOT fully sensitive 20% of hospitalized patients with suspected PID would not be included for immunologic investigation according to the 10 warning signs (Mehra 2007). 56% sensitivity, 16% specificity (Arkwright 2011)

There is now the "14 warning signs" that also include severe czema, allergies, hemtoonlgoic disorers, autoimmunity; this does improve the sensitivity but it's not perfect

There is some more nuance to the questioning:

• AGE at onset (before or after 6 months??)
  • also preterm or term (preterm might not have IgG from mom?) need to clarify
  • SCID presents EARLY, usually humoral takes time
• frequency (normal differs based on age)
• context behind each infection
• type: deep-seated, superficial; organism isolated?
• response to treatment, if needed

Unlike normal infections, those associated with ID may be:

• more than 12/year
• unusually severe / persistent; may be refractory to usual antibiotic therapy
• atypical presentation
• cause persistent damage
• may have recurrent infections with the same organisms
• may have infections with opportunistic microbes
• may have infections despite being given protective vaccine
• adverse response to live vaccines (ie active viral disease)

Some specific organ system pearls

• Otitis media:
  • early onset <3-4 months old
  • mastoiditis, brain abscesses
  • recurrence despite ear tubes or change to sinusitis
• Pneumonias
  • if >=2 X-ray proven:
    • Different lung sites?
    • • FHX or PIDD?
    • Known bronchiectasis or pneumatocele?

Some important FHx pearls

• ask about consanguinity in parents AND grandparents
• any sex related patterns?
• unexplained or early infant deaths or deaths due to infection/inflammation?

Now an approach to IEI

~500 different gene defects ... broad umbrella: see EUS clinical guidelines...

• cominbed B & T cell problems
• combined immunodeficiencies with associated or syndromic features
• predominantly antibody deficiencies
• immune dysregulation
• congential issues with phagocyte # function or both
• innate immunity
• autoinflammatory
• complement def
• bone marrow failure

A way to break it down could include:

• IEI
  • PIDD (infection predominant patho)
  • PIRD (Primary immune regulatory disorders), ie IPEX, IBD, malignancy

Category of IEI from infection types / pattern (not very specific, very simplified):

note: in the setting of PIDD or IEI things like serology are not particularly reliable for confirming infection; prefer direct measures such as cultures, DNA/RNA methods, direct antigen testing

predominantly antibody deficiency

After excluding 2' causes (ie. drugs, bone marrow issues, protein losses)

2 main phenotypes for hypogam:

• B cells are essentially absent (i.e. X-linked agammaglobulinemia)
• B cells >1%, CVID phenotype (MANY different monogenic defects possible, but not always found in 3/4)
  • If you look at the actual EUS guidelines there is further phenotypes of presentation within these that guide the differential as well

Other's that don't quite fit the above two:

• selective IgA def
• transient hypogam of infancy
• IgG subclass def with iga def
• isolated IgG subclass def
• antibody deficiency but normal B cell and levels ... reduced ability to produce antibodies to specific antigens

combined immune vs predominantly T cell

recall that B cells do need T cell to mature properly so T cell issues usually result in combined issues

Physical exam

Skin and appendages

Abnormal hair or teeth. Nail dystrophy. Absence of sweating. Eczema. Neonatal erythroderma. (Partial) albinism. Telangiectasia. Incontinentia pigmenti. Extensive warts or molluscae. (Congenital) alopecia. Vitiligo. Petechiae (early onset, chronic). Cold abscesses.

Oral cavity

Gingivostomatitis (severe). Periodontitis. Aphthae (recurrent). Giant oral ulcers. Thrush. Conical incisors. Enamel hypoplasia. Persistent deciduous teeth.

Eyes Telangiectasia.

Lymphoid tissue

Absence of lymph nodes and tonsils. Lymphadenopathy (excessive). Asplenia. Organomegaly (liver, spleen).

Neurological Ataxia. Microcephaly. Macrocephaly.

Other

Angioedema (without urticaria). Digital clubbing. Dysmorphism. Stunted growth or disproportional growth.

LACK OF LYMPHOID ISSUES IS KEY TO LOOK FOR

testing

[ { "categoryOfDisorder": "Cellular immune defect", "typicalInfectiousHistory": "Recurrent opportunistic infections, viral, fungal, bacterial, mycobacterial", "laboratoryInvestigations": "TRECALC, ALC (absolute lymphocyte count), Ly subsets enumeration (incl. CD45RA+), Ly function tests (mitogen/antigen prolif.), IgG, A, M, E, B cell functional antibodies (vaccine titres)" }, { "categoryOfDisorder": "Humoral immune defect", "typicalInfectiousHistory": "Recurrent sinopulmonary infections with encapsulated bacteria", "laboratoryInvestigations": "ALC, IgG, A, M, E, IgG 1–4 subclasses, B cell functional antibodies, isohaemagglutinins, B cell count/development by flow" }, { "categoryOfDisorder": "Neutrophil defect", "typicalInfectiousHistory": "Recurrent bacterial and fungal infections involving the skin and organs", "laboratoryInvestigations": "ANC (serial), smear, NBT/DHR, CD11/18 by flow" }, { "categoryOfDisorder": "Complement defects (early components)", "typicalInfectiousHistory": "Recurrent sinopulmonary and skin infections with encapsulated bacteria", "laboratoryInvestigations": "CH50 classical, AH50 alternate, (MBL) Level/function individual complement component" }, { "categoryOfDisorder": "Complement defects (terminal components)", "typicalInfectiousHistory": "Recurrent Neisseria infections", "laboratoryInvestigations": "CH50 classical, AH50 alternate, (MBL) Level/function individual complement component" } ]

Testing usually goes from: routine -> specialized -> research only

Quantity: – leukocyte subsets – lymphocyte subsets – Immunoglobulins (IgG,A,M,E, IgG subclasses) – complement factors (CH50class, alternate)

Quality/Function : – vaccine titres (protein/polysacch.), isohaemagglutinins – oxydative burst, adhesion molecules expression – lymphocyte proliferation – TCRvbeta repertoire – maternal chimerism – NK cell function (degranulation/killing) – plasma cytokine profile, IFN signature – etc..