newborn screening for SCID
T-cell receptor excision circles (TREC)
- >99% sens for classic and hypomorphic forms of SCID
- doesn’t screen for PIDs where normal amt of T cell receptors are created
CGD Management
- follow ESR and radiographs
- ppx antibiotics/antifungals: Bactrim, itra
- ppx IFN-g 3x/wk
- BMT or gene therapy
How to approach suspected T-cell defect:
- obtain lymphocyte subsets and ALC
- if ALC low in young age –> think SCID!!
- if ALC normal –> eval T-cell fxn (mitogens, Ags)
Dx of IFNgR deficiencye
genetics
flow cytometry
erythroderma
desquamation
organomegaly
eosinophilia
think Omenn syndrome
- can be d/t hypomorphic SCID mutations (e.g. reduced CD3+ T cell, <30% T-cell function)
- most often a/w RAG1/RAG2 defects
Complement Defects where AI disease is more common (SLE, DLE, etc)
C1-4 defects
What consider with disseminated NTM infections (or even with disseminated histo or cocci)
IFNgR deficiencies (AR more severe)
AR = complete defect, childhood, more severeAD = partial defect, later in life
most commonly implicated pathogens in complement deficiencies
encapsulated bacteria
- S pneumo
- H flu (type B)
- N meningitidis
how to approach suspected phagocytic defect:
- CBC, ANC
- if low ANC - consider cyclic neutropenia, AI neutropenia, referral to heme for BMBx
- if normal ANC - think CGD (obtain DHR burst testing), LAD (CD11/CD18 flow)
Dx and Tx CVID
- decreased IgG (total + subclass 1,3 or 2,4), IgA, IgM
- decreased response to new/recall immunization
Rx: treat infections, Ig replacement
mechanism of CGD
NADPH oxidase defects –> inability to produce superoxide anions
*inflamed tissue around uncleared pathogen creates granulomas
PID w/ increased predisposition to invasive candidiasis
CARD9 deficiency - familial candidiasis
with high IgE, think:
- Hyper IgE syndrome (Job’s)
- DOCK18 deficiency
Infections commonly seen in Chediak-Higashi syndrome
recurrent cutaneous and sinopulmonary infections
- GNR, staph, strep
- (no fungi)
Antibody-dependent bacterial lysis complement pathway
Defic: recurrent bacteremia and meningitis
Classical Complement Pathway (C1-9)
Defects to consider when:
- FTT
- skin rash
- diarrhea
- OI at any age
T cell defects
very common PID in adults - presents with recurrent respiratory and GI infections
think CVID
- low levels serum Igs, with decreased specific Ab response
- be sure to exclude other causes of hypoIg (much more common than CVID) - rx-induced, infection, malignancy
Defects to consider when:
respiratory/GI sx after 1st few mos of lifeenterovirus meningoencephalitisrecurrent sinusitis, pnas, bronchiectasis
think B-cell defects (usually present after maternal Abs wane)
Complement Defect
recurrent neisseria BSI/meningitis
(typically 17yo, mild CNS)
C5-9 defects
thrombocytopenia (Decreased MPV)
eczema
recurrent infectionsoften with autoimmunity or malignancy
Wiskott-Aldrich syndrome
d/t mutations in WAS protein (WASP)
hyper IgE (97% >2000)
eosinophilia (93% >2SD)
think HIE
no correlation b/w IgE and eos)
essential cells for killing of fungi
phagocytes (neuts, monos, macrophages, eos, basos)
- teen/adult onset
- recurrent HPV infections
- disseminated NTM (esp mediastinal M kansasii)
- pancytopenia: w/ profound monocytopenia - low B, low NK)
- CT - subpleural blebs
think GATA2 deficiency
Dx: genetics, hypocellular marrow
Deficiency responsible for leukocyte adhesion deficiency 1
CD18 → loss of integrins
Primary immunodeficiencies a/w increased predisposition to EBV
**Chronic EBV viremia, EBV-assoc lymphoproliferative d/o
- ITK def
- MAGT1 def
- STK4 def
- CD27 def
- Coronin-1A def
lab definition of SCID
- T-cell count <300 +
- absence of T-cell response to mitogens (<10% compared w/ control)
Diagnostic tests for complement defects
CH50 - Classical
AH50 - Alternative
Eczema
allergies
asthma
High IgE
HPV, HSV, molluscum
Candida, crypto, histo
pseudomonas
think DOCK8 deficiency
(more GN and more viral infections than with Job’s)
recalcitrant, severe HPV
also think with NTM
**does not have other features of Job’s: retained teeth, path fx, pneumatoceles
Defects to consider when:
Cellulitis w/o pus
granulomas
IBD
liver abscesses
prolonged attachment of umbilical cord
phagocytic defects
SCID
megaloblastic anemia
atypical HUS (sometimes)
think methylenetetrahydrofolate dehdyrogenase def (MTHFD1)
Most common Ig deficiency
IgA
not often detected, not a/w disease (though can be a/w other deficiencies like CVID and other Ig subclass deficiencies)
Confirm dx of IFNgR1 deficiency
show high IFNgR1 on cell surfaces (truncated, so can’t be taken off)
When to consider hyper IgE (HIE) Job’s syndrome
- recurrent sinopulmonary infections (SA, SP, H flu)
- post-infections pulm cyst formation
- recurrent SA skin abscesses
- characteristics: facies, eczema, scoliosis, path fx
- very elevated IgE (>2000), eosinophilia
- Mutation of STAT3
most common presentation of CD40 ligand deficiency
PJP pneumonia
other common: cryptosporidium, cryptococcus
GI disease (diarrhea, liver dysfunction)
high risk of lymphomas, liver cancers
Infections in chronic granulomatous disease
Catalase-positive bacteria
Fungi
–> Tissue granuloma formation
common infections seen with CVID
- recurrent sinu-pulm infections
- chronic enteric infections (giardia, campy, salmonella, shigella)
- severe echoviral meningitis/encephalitis, myositis
screening labs for phagocytes
DHR - for superoxide
FACS - CD18, CD11a-c, IFNgR1, IL-12RB1
associated with antibody-negative pulmonary alveolar proteinosis (PAP)
GATA2 deficiency
PIDs with increased predisposition to mycobacterial infections
- IL12 deficiency
- IL23 deficiency
- IFNgR deficiency
- Teeth loss, gingivitis
- Impaired wound healing
- Dystrophic “cigarette paper” scars
- Delayed umbilical stump separation
- Often no purulence seen
- (bx w/o neutrophils at site of infection)
think LAD1
neutropenia, splenomegaly + often RA
Felty syndrome
- GOF in STAT3
- large granular lymphocytosis
How to approach suspected B-cell defects
- obtain lymphocyte subsets and ALC
- if low ALC - ?combined ID - target T-cell eval
- if normal ALC - obtain B-cell number, quant Igs, Ab response to vaccines
- absent B cell early age - think XLA
- abnormal number/function - XLA, hyperIgM syndromes, CVID
- adult onset - CVID
Infections common with LAD1
- recurrent necrotizing infections: skin, perineum, lung, gut
- GPC, enteric GNR (NOT fungal)
**will have baseline leukocytosis (sometimes as high as 100 with infection)
high IgM
low/absent IgG, IgA, IgE
CD40 ligand deficiency
- CD40 ligand expressed on activated CD4 T cells (CD40 on B-cells)
- –> CD4+-deficient patients (CD4 cells non-functioning)
- interaction required for B cell survival, growth, differentiation (IgM not able to class-switch)
- Eczema
- Abnormal facies (increased nasal width)
- recurrent boils
- recurrent PNA –> pulmonary cysts
- scoliosis
- delayed dental deciduation
- coronary artery aneurysms
- pathologic fractures
think HIE (Job’s) syndrome
*pulmonary cysts will form after infection, even with adequate tx – often get 2ary infected
giant granules in neutrophil
Chediak-Higashi syndrome
(mutations in Lyst - cause giant primary and fused secondary granules within the cytoplasm of neutrophil)
Diagnosis of CGD
Preferred: PMN DHR (dihydrorhodamine 123 oxidation)
PMN nitroblue tetrazolium reduction (NBT)
– results from failure to produce superoxide and its metabolites
most common severe PID
SCID (1/60k live births)
results from many different genetic defects
recurrent sino-pulmonary bacterial infections
CVID
Complement Pathway with Ab INdependent bacterial lysis
Defic: severe disease
Alternative Pathway (Factors I, H, properdin, C3)
–> protects before Abs enter the picture
infections a/w CGD
nearly pathognomic = infections with rare catalase+ orgs:
- granulibacter bethesdensis
- chromobacterium
- francisella
burkholderia
nocardia
aspergillus (look for in non-neutropenic pt)
PIDs with increased predisposition to chronic mucocutaneous candidiasis
- IL-17 deficiency
- autoimmune polyendocrine candidiasis ectodermal dystrophy (APECED) - CMC, Addison, hypoparathyroid, metaphyseal dysplasia
PIDs with increased predisposition to HPV
- epidermodysplasia verruciformis - disseminated flat, wart-like papules
- CXCR4 def - myelokathexis (retention of neuts in bone marrow) + hypoIgs + warts
- DOCK8 def - hyperIgE + eos, severe viral skin infections
- GATA2 def - not as much as DOCK8. monocytopenia, NK def, pulmonary alveolar proteinosis
Criteria for HLH
(5 of 8 required) *prolonged, excessive activation of AP and cytotoxic cells d/t inability to clear inciting pathogen –> cytokine storming
- fever
- SM
- cytopenias (Hgb<9, plt <100, ANC <1K)
- TG >265
- fibrinogen <150 (low)
- ferritin >500
- IL-2 receptor (>2400) - marker of T-cell activation
- low/absent NK activity
- hemophagocytosis on path
- disseminated NTM later in life
- female
- East Asian (born there)
Anti-IFNg autoantibody syndrome
Dx w/ autoAb detection
common clinical manifestations of Chediak-Higashi
- Infections (Bacterial, not fungal)
- Mild neutropenia (d/t intramedullary destruction)
- Partial oculocutaneous albinism
- Mental retardation
- Neuropathy
- Lymphoma/HLH-like phase
PIDs with increased predisposition to cryptosporidium
IL-21 receptor def - chronic cholangitis and cirrhosis d/t prolonged cryptosporidium infection
Only part of immune system to control aspergillosis
- phagocytes (neuts, monos, macrophages, eos, basophils)
- In otherwise normal host = aspergillosis means phagocytic defect
dx/tx Chediak-Higashi
Dx: giant blue granules w/in neut
Mutation in CHS1 (encodes Lyst)
Rx: bacterial ppx (Bactrim), tx infections, ?BMT
Defects to consider with:
- strep, neisseria infections
- rheumatoid disorders
complement deficiencies