Primary Immunodeficiencies: non-infectious complications - 2018 WSAAI update

This is a Twitter summary from the 2018 WSAAI meeting. This summary was compiled from the tweets posted by @MatthewBowdish, an allergist/immunologist, who attended the 2018 Western Society of Allergy, Asthma and Immunology (WSAAI) meeting. The tweets were labeled #WSAAI. The text was edited and modified by me.

Thomas Fleisher on "Primary Immunodeficiencies: more than just recurrent infections".

There are 2 groups of CVID patients:

1. Infections without complications (1/3): nml life expectancy, effective IgG replacement = good QoL

2. Infections plus other complications (2/3): autoimmunity (30%), GI (15%), granulomatous disease (10%), lymphoma (8%), splenomegaly (30-40%), lymphadenopathy (15%).

Autoimmunity in CVID: https://twitter.com/MatthewBowdish/status/956665155894484992

Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD): 10% CVID; median diagnoses age is in the 4th decade; granulomas can also involve LNs, liver, GI; imaging shows "halo sign" with parenchymal disease more in lower lung, +bronchiectasis; PFT shows restrictive lung disease.

Treatment of GLILD involves immunosuppression, eg rituximab and azathioprine.

Poorer outcomes in CVID associated with presence of non-infectious complications, early age of onset and biomarkers that negatively affect outcome (high IgM and lower IgG at dx, low B cells).

Monitoring CVID patients: https://twitter.com/MatthewBowdish/status/956667548577103872

CVID and CVID-like disorders with defined genetic causes often are associated with findings on immune dysregulation.

CVID plus complications have a poor outcome: https://twitter.com/MatthewBowdish/status/956668257586442240

Do we consider other, more aggressive treatments like bone marrow transplants for these patients?

Newer biomarkers in CVID:

1 - switched (IgD-) memory (CD27+) B cells showed increase risk of granulomas and splenomegaly.

2 - low B cells in US study of CVID patients associated with risk of autoimmunity and lymphoma.

Dr. Charlotte Cunningham Rundles has seen 43 lymphomas in her cohort of 650 CVID patients - Her take home is TAKE NEW COMPLAINTS/CHANGES SERIOUSLY.

CVID-like diseases

Heterozygous (AD) CTLA-4 Mutations are CVID-like: https://twitter.com/MatthewBowdish/status/956670292369158144

CTLA-4 mutations lead to immune dysregulation through Treg dysfunction. Treatment for CTLA-4 haploinsufficiency treated with rapamycin, targeted therapy with a CTLA4 agonist (CTLA4-Ig/Abatacept) and possibly hematopoietic stem cell transplantation.

Other CVID-like diseases include LRBA mutations, gain of function mutations affecting p110delta subunit of phosphatidylinositol-3-OH kinase (PIK3CD), and AR mutations in PIK3R1.

Currently, around 30% of CVID-like patients are now found to have either a monogenic cause (eg CTLA4, PIK3CD) or monogeneic susceptibility (eg TACI).

Thomas Fleisher also reviewed Omenn Syndrome, RAG deficiency, IPEX, IL10/IL10 Receptor Defects, and APECED.

Diagnostic Evaluation of low IgG:

- Serum IgG between 450 mg/dl and 600 mg/dl. Repeat serum immune globulins for verification. Test antibodies to tetanus and diphtheria and also other protein based vaccines (measles mumps rubella, H zoster) also non conjugated pneumococcal vaccine and test 4 weeks post vaccination.

- Serum IgG between 250 and 450 mg/dl. Repeat serum immune globulins for verification. Test antibodies to tetanus and diphtheria or other protein based vaccines; also non conjugated pneumococcal vaccine and test 4 weeks post vaccination.

- Serum IgG between 150 and 250 mg/dlL. Repeat serum immune globulins for verification; Consider testing antibodies to tetanus and diphtheria or other protein based vaccines; optional, non conjugated pneumococcal vaccine and test 4 weeks post vaccination.
- Serum IgG under 150 mg/dl. Repeat serum immune globulins for verification; no antibody testing required.

References: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904582/

Monitoring of patients with CVID:

- All patients with CVID: Every 12 months Interval history, physical examination, height and weight. Complete blood counts: Hgb, Hct, white blood cells and differential, platelets, and chemistry panel including liver and kidney functions; albumin. Spirometry. Every 6 to 12 months or with weight gain: Serum IgG, consider adding IgA and IgM. Consider chest X-ray at the time of diagnosis.

- CVID patients with lung disease: High Resolution Chest CT every 3 – 4 years or after change of therapy. Complete lung functions with CO diffusion every 12 months.

- CVID patients with with gastrointestinal complications: Upper and/or lower Endoscopy based on GI recommendations.

- CVID patients with evidence of malabsorption including loss of height; women in particular: Bone density, evaluation of nutrients based on history.

References: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904582/

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