Suspecting Immunodeficiency - Health Education England

Suspecting Immunodeficiency - Health Education England

Suspecting Immunodeficiency David Lowe Royal Free Hospital / University College London Or Suspecting primary immunodeficiency AND

Suspecting secondary hypogammaglobulinemia Primary immunodeficiency (in adults) Antibodies / B cells (XLA) CVID IgA deficiency

(+/- Specific Ab def, IgG subclass def etc) T cells Mild phenotype SCID Idiopathic CD4 lymphopenia Phagocytes CGD Complement

A few other rare ones Dissecting Ab deficiency Hyper IgM syndrome

-Reg -Reg X CTLA4 def

IPEX Connecting Ab deficiency with autoimmunity Antibodies (not auto-!) Opsonise micro-organisms Improve phagocytosis

Improve recognition by other immune cells Activate immune responses & complement Infectious consequences of Antibody deficiency Sino-pulmonary infection URTI LRTI bacteria and viruses

Sinusitis Ear infections Can end up with bronchiectasis / complications thereof GI infections, including Giardia Sepsis, meningitis, osteomyelitis Not especially skin & urine infections Prolonged / severe infection with normal pathogens, eg norovirus

Autoimmune complications in CVID Autoimmune cytopenias +/- splenomegaly Granulomas Interstitial lung disease Enteropathy NRH / liver fibrosis

Arthritis Lupus-like features Cunningham-Rundles. Hematology Am Soc Hematol Educ Program, 2012:301-305 28.6% of cohort had autoimmunity Autoimmunity in IgA deficiency

20 30% have autoimmune disease SLE, Graves disease, T1DM, (juvenile) RA ?Myaesthenia, ?IBD Coeliac disease approx. 8% Autoantibodies very common (up to 90%) May be more clinically important than sino-pulmonary infections (bronchiectasis rare) & Giardia

A few pictures. So check the immunoglobulins! A couple of specific disorders

Disorder Features Clue GATA-2 deficiency

MDS, NTM infection, malignancies No monocytes! IL-17 pathway defects (eg STAT1 GOF)

Fungal infections (CMC) Oral thrush with no other reason CARD-9 deficiency

Fungal infections Oral thrush, invasive dermatophyte infection Th 1 cytokine pathway

defects NTM infection, listeriosis etc NTM with no other reason, often young

APECED Polyendocrinopathy (inc AIH), vitiligo Oral / persistent thrush ALPS

Lymphadenopathy, splenomegaly, AIH, GN, uveitis, lupus Lymph nodes, doublenegative T cells ALPS pathogenesis = Fas mutation

T cell Mr T cell Secondary hypogammaglobulinemia Medication

B-CLL (+ other lymphoproliferative diseases) Protein loss Table 2. Likely cause of secondary antibody deficiency in each subject. Duraisingham SS, Buckland M, Dempster J, Lorenzo L, Grigoriadou S, et al. (2014) Primary vs. Secondary Antibody Deficiency: Clinical Features and Infection Outcomes of Immunoglobulin Replacement. PLoS ONE 9(6): e100324.

doi:10.1371/journal.pone.0100324 Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. Makatsori M et al. QJM 2014; 107:821-8. So check the

immunoglobulins! (before and after Rx) A couple of pitfalls with IVIG N = 80 N = 17

Are these results for: A: Troponin B: Hepatitis B core Antibody C: Attitude to treating Immunologist Serology is useless

on IVIG! Galactomannan 3 2 1 0


4 0.4 0.2 0.0

CGD Consequences of CGD Bacterial infections, esp with catalase-positive organisms (eg Staph aureus, Burkholderia cepacia, Serratia marcescens)

Folliculitis, Skin abscesses Liver abscesses Fungal infections, esp Aspergillus pneumonia Nocardia; atypical mycobacterial infection Granulomatous colitis, fistulae etc Often dominant in variant CGD

Abnormal inflammatory responses leading to obstructive swelling GI obstruction, esp gastric outflow GU obstruction CGD carriers Some infections

Mouth ulcers Photo-sensitivity Cutaneous lupus-like lesions Arthralgia / arthritis Chorioretinitis Mechanism unknown - ? Poor clearance of apoptotic cells

A few more pictures. Chronic granulomatous disease carrier geno-dermatosis (CGDCGD), (Finlay et al, Clinical Genetics 1983; 23:276280.)

Key messages Have a low threshold for checking immunoglobulins Remember the secondary causes of hypogammaglobulinemia Dont do serology if people are on IVIG! Look for the clues of immunodeficiency THANKS!

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