Jonathan Tam, MDClinical Division of Allergy and Immunology

Children’s Hospital Los Angeles

Recognizing Immunodeficiency & Immune Disorders in Adults

October 15, 2020

In accordance with the ACCME policy on relevant financial disclosure, all speakers/planners were asked to reveal any relevant financial relationships.

Research supportRegeneronAstra Zeneca

Disclosures

Learning Objectives

• To recognize signs and symptoms of potential immunodeficiency

• To review immunodeficiencies that can be found in adults

• To review basic evaluation of patients with suspected immunodeficiency

Outline

• Basic immunology

• Primary Immunodeficiency (PIDD)• Newborn Screening

• Example of adult onset immunodeficiency• CVID

• Anti-cytokine autoantibodies

Immunology ReviewJust a Touch

Figure 1-1, Abbas, A. K., et al. "Cellular and molecular immunology, Elsevier Saunders." Eighth Edition. Philadelphia, PA.(2015).

Innate and adaptive immunity

COMPARTMENTS OF IMMUNITYH

UM

OR

AL

CE

LLU

LAR

INNATE ADAPTIVE

Macrophages

Phagocytes

Neutrophils

NK cellsT cells

B cells

Antibody

CD4

CD8

Complement Spleen

Primary Immunodeficiency in ChildrenJust a Touch

PRIMARY IMMUNODEFICIENCES

11

Dosanjh, Amrita. Pediatrics in review 36.11 (2015): 489-94.

PIDs prevalence ~ 1:10,000 to 1:12,000 live births

-vary from common ~1:500 for IgA deficiency to rare ~1:200,000 in CGD to v. rare in LAD ~1:1 million

Antibody deficiencies are the most common

Incidence of Severe combined immunodeficiency (SCID) ~ 1:58,000 live births in the US

Diseases of innate immunity (including NK cells), and complement deficiencies are most rare

When do primary immunodeficiencies typically present?

• Antibody defects typically present after 4-6 months (after maternal antibodies are depleted)

• Cellular defects generally present within the first year of life

• Combined (B- and T-cell) defects can present at any time…

PIDD in Children

Children with a normal immune system can average 6-8 upper respiratory

infections (URI) per year

Can be as high as 10-12 URIs per year with various risk factors:

- siblings, day care/preschool, asthma, chronic disease, atopic disease

Mean duration of viral URI symptoms ~8 days, but can extend >2 weeks

-So a “normal” child with >10 URIs per year can potentially have symptoms half the year

‘10 Warning Signs’ of Primary Immunodeficiency (PID) by Jeffrey Model

Foundation

- Can be helpful but just a guide as most signs not very sensitive or specific13

14

http://www.info4pi.org/library/educational-

materials/10-warning-signs

SCID Newborn Screening

Justification for SCID Newborn Screening

SCREENING CRITERIA

• Disease is serious

• Disease is not detectable by routine exam

• Incidence supports screening• (hypothyroidism 1:2,000, galactosemia

1:88,000)

• Simple, reliable test is available

• Confirmation test is available

• Treatment alters disease

• Earlier treatment improves outcomes

SCID MEETS CRITERIAFatal if untreated

SCID babies appear healthy at birth

~1:50,000

TREC

Lymphocyte subset analysis

BMT/HSCT cures SCID

Survival improved if BMT/HSCT done before complicating infections

T-Cell Receptor Excision Circles (TREC)

• Small circles of DNA

• By-products of T-cell receptor (TCR) gene rearrangement during generation of antigen specific TCR in the thymus

• Effectively looks for naïve T cells and screens for T cell lymphopenia

• Stable, detectable and quantifiable

• TREC ≈ T-cells

• Actin gene = control

T-Cell Receptor Excision Circles (TREC)

3 mm hole punched from blood spot

~3 ul blood

Measure TRECs by PCR

Extract DNA

50 ul blood/drop

Guthrie Card

TREC DRIED BLOOD SPOT ASSAY

General Warning SignsBack to Including Adults

Symptoms of Immunodeficiency

• Infections• Frequent, severe, unusual, resistant organisms

• Often common infections that are hard to eradicate

• Autoimmune disease• Immune system no longer able to properly distinguish “self” from “non-self”

• Immune dysregulation• Unchecked immune cell proliferation

• Hematopoietic malignancy

• Impaired tumor surveillance

Mimickers of Immunodeficiency

• Infection• HIV – destroys T-cells (CD4+)

• Malnutrition• Vitamin deficiencies, thymic involution

• Smoking • Ciliary dysfunction

• Loss of barrier function• Burns, influenza with superinfection (secondary pneumonia)

• Medications• Corticosteroids, immunosuppressants

• Genetic Causes• Cystic fibrosis, primary ciliary dyskinesia• Splenic dysfunction (Sickle Cell disease, congenital asplenia)

COMPARTMENTS OF IMMUNITYH

UM

OR

AL

CE

LLU

LAR

INNATE ADAPTIVE

Macrophages

Phagocytes

Neutrophils

NK cells T cells B cells

Antibody

CD4

CD8

Complement Spleen

INFECTIONS / ASSOCIATIONS

24HU

MO

RA

L

CE

LLU

LAR

INNATE ADAPTIVEPhagocytes

Complement

T cells

Staph pyoderma infectionAbscessesSevere “eczema”

Persistent thrushFungal / OpportunisticSevere HSV/VZVChronic diarrheaFailure to thrive

PneumoniaOtitis mediaSinusitisChronic diarrhea

Recurrent sepsisRecurrent meningitisSystemic Neisseria infection

Antibody

B cells

Spleen

Key DISORDERS to considerH

UM

OR

AL

C

ELL

ULA

R

INNATE ADAPTIVEPhagocytes

Complement

T cells

Chronic Granulomatous Disease Hyper IgE

SCID or other CID DiGeorge syndrome HIV / AIDS

25

Terminal Complement deficiency (C5-C9)

Antibody

B cells

SIGAD THI SAD CVID XLA

Spleen

Hyposplenism

Initial outpatient screenH

UM

OR

AL

C

ELL

ULA

RINNATE ADAPTIVE

Phagocytes

Complement

T cells

CBC w/diff Phagocyte oxidase activity

Dihydrorhodamine (DHR) or

Nitroblue-tetrazolium (NBT)

CBC w/diff IgG, IgA, IgM, IgE Tetanus and Hib antibody levels HIV antibody or PCR

26

CH50 CBC w/diff with smear

for Howell-Jolly bodies

Antibody

B cells

Spleen

CBC w/diff IgG, IgA, IgM, IgE Tetanus and Hib antibody levels HIV antibody or PCR

Two Examples

Common Variable Immunodeficiency (CVID)

CVID

• Primary immunodeficiency of unknown etiology*.• Mutations in TACI in approximately 10%• Increased risk of CVID—sibs with identical mutations but

without disease• Most cases not inherited (family member with IgA deficiency in 8-

10%, some linkage to MHC)• Incidence is uncertain: estimated 1:30,000 to 1:50,000 (under

diagnosed!!!)

* Small numbers of patients dx with CVID have mutations in BTK, SH2DIA (SLP), TACI and ICOS.

J Allergy Clin Immunol Pract 2016;4(1):38-59

CVID (ICON) 2016 Consensus Definition1. At least one of the characteristic clinical manifestations (infection,

autoimmunity, lymphoproliferation)

2. Hypogammaglobulinemia according to the age-adjusted reference range in at least 2 measurements more than 3 weeks apart.

3. IgA or IgM level must also be low.

4. Decreased/absent ability to make specific Abs (polysaccharide Ags> protein Ags)

5. Other causes of hypogammaglobulinemia must be excluded.

6. Genetic studies to investigate monogenic forms of CVID

CVID

• Delay in dx common--4 to 8.9 years—(Clin Exp Immunol. 147: 306-12, 2007; J Clin Immunol. 27:308-316, 2007, J. Ped. 154:888-94, 2009)

• Index of suspicion needs to be MUCH higher.

• Minimal workup: Quantitative immunoglobulins are indicated in any person with 2 or more CXR-documented pneumonias requiring Abx

CVID: Clinical Presentation

• Recurrent Upper/Lower RTI-most common presenting symptom

• Think Ab deficiency in patient >1 pneumonia, intractable sinusitis, recurrent otitis media

• GI Tract Infections also common (Giardia, enteroviruses)

• Think Ab deficiency with intractable or recurrent GI infections with giardia

• Less common: meningitis, septicemia, osteomylelitis

• Autoimmunity, increased malignancies in some forms of Ab deficiency

CVID: Common Bacterial Pathogens

• Encapsulated bacteria (S. pneumoniae, H. influenza)• GNR in patients repeatedly Rxd with antimicrobials

• Atypical bacteria (Mycoplasma sp., Ureaplasma sp.)• Unique susceptibility—must cover these organisms when Rx

URTI (acute sinusitis) or LRTI

Inflammatory or autoimmune manifestations of New York CVID cohort

Ann Allergy Asthma Immunol. 2019 Nov;123(5):454-460.

Autoimmunity in CVID cohort of USIDNET

J Clin Immunol, 38 (2018), pp. 28-34

REMINDER: Diagnostic Studies in Patients with CVID and antibody defects (or people on IVIg)

• DO NOT use serological assays for dx in pts. with CVID, XLA or other forms of panhypogammaglobulinemia

• Serological assays: measure antibodies in gammaglobulin in patients receiving IVIG

• Dx of infectious disease MUST be done by culture, PCR or other direct methods to directly test the presence of the pathogen

Anti-cytokine AutoantibodyA class of disorders

The Story of NTMWhen it looks like Primary Immunodeficiency, but…

60 yo Vietnamesefemale

Moved to USA 1970s

1 year recurringdisseminated M. avium complex

Numerous fistulae

CASE: Disseminate NTM

Mycobacteria

Relative Virulence

M. tuberculosis

M. kansasii

M. leprae

M. avium complex

M. abscessus

M. gordonae

M. smegmatis

Bacille Calmette-Guerin

M. fortuitum

Koch, 1882

NTM

Clinical Spectrum of NTM Infections

Disseminated

Severe, Young

Immune defects

Pulmonary

Chronic, Older

Bronchiectasis

Cystic fibrosis (CF)

Ciliary dyskinesia (PCD)

SkinExposure

Inoculation

T/NK Cell

Macrophage

IFN γ R

IL-12R

Mycobacterial Control

IFN γ

IL-12

Mendelian Susceptibility to Mycobacterial Disease (MSMD)

Pathogens in human IFN γ /IL-12 defects: Intracellular Pathogens

Nontuberculous mycobacteria (NTM)

Bacille Calmette Guerin (BCG)

M. tuberculosis (MTB)

Salmonella

Burkholderia

Listeria

Histoplasma

Coccidioides

VZV, CMV, HSV, HHV-8

RSV

What is Causing this Late Onset Immunodeficiency?

The infections suggest IFNg/IL-12 pathway.

The age is late for a typical primary immunodeficiency.

Genetic testing did not find a cause.

Clin Infect Dis. 2000 Jan;30(1):29-34.

59 Adult Thai Cases of NTM with Coinfections

Disseminated Penicillium marneffei

M. fortuitum

Salmonella lymphadenitis

Cryptococcosis

M. abscessus

Neutrophilic pustulosis

Sweet Syndrome (acute febrile neutrophilic dermatosis)

NEJM 2012;367:72590% of Thai patients with severe NTM infection had neutralizing anti-IFNγ autoantibodies

7

6

5

4

3

2

Only anti-IFNg Autoantibodies AreAssociated with Disseminated NTM

41 autoantibodies tested by LIPS (Luciferase)

Anti-IFNg

T/NK Cell

Macrophage

IFN γ R

IL-12R

Mycobacterial Control

IFN γ

IL-12

Autoantibodies IFN γ

• Mostly adults from age 40-70

• Susceptible to severe or disseminated NTM, salmonella (29-40%), VZV

• Almost all patients with anti-IFNγ mostly in Southeast Asia and Japan• HLA association?

Human Genetics volume 139, pages783–794(2020)

Autoantibodies to CytokinesIn sufficient concentration, anti-cytokine autoantibodies could block the signaling or neutralize the biological function of target cytokines via:

preventing the direct binding to its receptor and/or

depleting the cytokine through forming a cytokine/autoantibodies complex

Unknown stimulus, external exposure leading to cross-reactive antigens or multi-step breakdown of tolerance?

CASE: CNS Nocardia

43-year-old male

Acute seizure

Brain biopsy: pus

Culture: Nocardia

Chest CT: Rare ground glass

opacities

Pulmonary function: normal

J Immunol 2013, 190 (8) 3959-3966

mBio 2014;5:e00912-14

Anti-GM-CSFAutoantibodies

ONLYin C. gattii

Anti-GM-CSF in Plasma of CNS Nocardia Patients

Flu

ore

scence I

nte

nsity

GM-CSF

G-CSFIFNαIFNβ

IFNωIFNγ

IFNλ1

IFNλ2

IFNλ3

IL-1αIL-4IL-6IL-7

IL-10

IL-12p70

IL-15

IL-17A

IL-17F

IL-22

IP-10

TNFα

TNFβ

0

5000

10000

15000

20000

25000

Autoantibodies to GM-CSF

• Anti-GM-CSF autoantibodies in pulmonary and meningeal cryptococcosis and Nocardia

Anti-cytokine Autoantibody Treatment

• Antibiotics/antifungals

• Rituximab

Both groups lack effective immune responses that depend on type I interferon.

Interferons

• Interferon type I: The type I interferons present in humans are IFN-α, IFN-β, IFN-ε, IFN-κ and IFN-ω. In general, type I interferons are produced when the body recognizes a virus that has invaded it. They are produced by fibroblasts and monocytes.

• Interferon type II (IFN-γ in humans): This is also known as immune interferon and is activated by Interleukin-12.

• Interferon type III: Discovered more recently than type I and type II IFNs, important in some types of virus or fungal infections.

Science. 2020 Sep 24;eabd4585. doi: 10.1126/science.abd4585.

More than 10% of people who develop severe disease have neutralizing autoantibodies against type I interferon.

• Another 3.5% or more carry a specific mutation that impacts immunity.

• TLR3, TICAM1, TBK1, IRF3, IRF7, IFNAR1, IFNAR2

Science. 2020 Sep 24;eabd4570. doi: 10.1126/science.abd4570.

Cytokine Autoantibodies Summary

Cytokine Susceptibility Note

Type 1 Interferon (IFNa, IFN⍵)

SARS-CoV2, Influenza

Type 2 Interferon (IFNγ)

Nontuberculous mycobacteria

GMCSF Pulmonary and meningeal cryptococcosis (gattii) and Nocardia

pulmonary alveolar proteinosis

IL6 Severe bacterial infection, pyogenic infection low CRP despite infection

TH17 cytokines (IL17A, IL17F, IL22, IL23)

Fungal infections, mucocutaneous candidiasis

Conclusions

• Immunodeficiencies can present in adulthood

• Keep a high index of suspicion

• CVID may present with inflammatory of autoimmune manifestations

• Anti-cytokine autoantibodies may explain poor response to specific infectious diseases

• New diagnostic testing may open new therapeutic options

Thank youQuestions?