Current Concepts in the Diagnosis and Management of CVID and

Specific Antibody Deficiency (SAD)

John Sleasman, M.D. Professor and Chief Division of Allergy and Immunology Department of Pediatrics, Duke School of Medicine 1

Objectives: • To know the clinical and laboratory criteria in

making the diagnosis of antibody deficiency diseases.

• To understand the interpretation of diagnostics tests for CVID and specific antibody deficiency.

• To be able to recognize the non-infectious complications of CVID and SAD.

• To be able to implement plan for monitoring and treating patients with CVID and SAD.

•

COPD and recurrent infections • 42 WF non- smoker with diagnosis of

COPD • Chronic sinusitus, recurrent bacterial

pneumonia requiring treatment with IV antibiotics

• FEV1- 64% predicted with little reversibility

• History of thrombocytopenia and splenomegaly

Bilateral, diffusely distributed nodules in lung and liver, mediastinal lymphadenopathy, bronchiectasis biopsies shows non-caseating granuloma

The Specialists • What does this patient have?

– Her Rheumatologist said sarcoidosis.

– Her oncologist suspected cancer.

– Her pulmonologist said COPD.

– She said “to H#&!* with you guys!”

Immunology Evaluation – After nearly ten years of persistent symptoms and

progressive bronchiectasis an immune evaluation was performed.

– Immuneglobulins Levels • IgG 154 (613-1295 mg/dl) • IgA < 5 (69-309 mg/dl) • IgM 10 (53-334 mg-dl)

– Low T cell numbers, inverted CD4/CD8 ratio – No functional antibody titers to tetanus, diptheria, or

pneumococcal polysaccharide – HIV antibody testing was negative – B cell enumeration was normal at 15%

– DIAGNOSIS: Common Variable Immunodeficiency

The Road to Immune Perdition

Genetics

Chronic Pathogen Exposure

Immune Dysfunction

Infection Autoimmunity Malignancy

Localized Inflammation

Chronic Infection

Systemic Disease

CVID’s Non-infectious Outcomes

Autoimmunity

Malignancy

CVID Diagnostic Criteria • Absent/low antibody production and function

– IgG and at least one other isotypes 2 years, both males and females • Presence of B cells (normal or low) • Exclusion of other causes of immune deficiency • Clinical manifestations:

– Recurrent sinopulmonary infections (90%) – Gastrointestinal infections/IBD (25%) – Autoimmunity/Granulomatous disease (20%) – Malignancy (10%)

Ann Allergy, Asthma, Imm (May 2005)

Common Features of CVID Pathogenesis

• Defective B cell maturation and activation – Reduced CD27+ memory B cells

• Variable low Immunoglobulin levels • Defective response to immunization

– T cell co-stimulation – T cell dependent and independent antigen

response impaired

Salzer, Seminars in Immunology, 2006

Genetic Clues

• CVID represents a group of heterogeneous disorders

• Shared CVID phenotypes with known genetic pathogenesis – atypical BTK, SAP variants of XLP, TACI, ICOS

deficiency, CD19 mutations, subtypes of AR hyper IgM (HIM gene mutations in AID or UNG)

Ann Allergy, Asthma, Imm (May 2005)

Newly Identified CVID Variants

• CD27 mutations: CVID EBV driven lympho-proliferative disease

• PLCG2: CVID –Auto-inflammatory disease –Cold urticaria

• NLRP12 –CVID with intestinal amyliodosis

• NFKB2: –CVID

•••••••• CCCCCCCCD2

Newly Identified CVID Variants

• PIK3CD: –CVID Ig profile, elevated IgM –Decrease naïve CD4, increase CM

CD8, inverted CD4/CD8 ratio –Herpes virus driven lympho-

proliferative disease –Sinopulmonary infections

Newly Identified CVID Variants

• PIK3CD: –CVID Ig profile, elevated IgM –Decrease naïve CD4, increase CM

CD8, inverted CD4/CD8 ratio –Herpes virus driven lympho-

proliferative disease –Sinopulmonary infections

When to Consider Aggressive Genetic Assessment

• Whole exome sequencing can be expensive and results confusing

• Phenotype needs to be defined – Clinical – Laboratory

• Family history and 1st degree relatives should be available

Assessing the etiology of non-infectious complications of

CVID

• Autoimmunity • Malignancy

CVID-associated Autoimmune Disorders

• Hemotologic (11% of all CVID) – ITP (younger patients, 50 years) – Evans Syndrome

• Endocrinopathy (5%) – Pernicious anemia, autoimmune thyroid disease

• Gastrointestinal (25%) – IBD, sprue, nodular hyperplasia, biliary cirrhosis

• Systemic Disease (5%) – RA, Sjogrens, SLE, vasculitis, polymyositis

Cunningham-Rundles, Clin Imm, 1999

Granulomatous Disease in CVID

• Sarcoid-like illness – granulomas in lung, liver, LN, spleen – elevated ACE

• Incidence 5 to 20% of CVID • Autoimmune thrombocytopenia and

neutropenia common • Disease progression common

Morimoto, Cur All & Asthma Report, 2005

Clinical Manifestations • Lymphadenopathy, HSM

– Granuloma within HRCT – reticular nodular infiltrate in lower lung, bronchiectasis

• PFT-Restrictive lung disease – Low FVC, low FEV1, low DLCO

• Non-caseating granuloma in liver, spleen, LN, GI trat, CNS, parotid, eye, kidney

• LIP, lymphoproliferative disease

CVID Granulomatous Disease • Chronic immune activation/inflammation

– Elevated acute phase reactants – T and B cell activation

• Low T cell numbers, HLADR, CD8/CD57 • Increased TNFά, B cell proliferation

• High risk of progression to NHL • Poor prognosis in over 50% of patients • Disease not seen in XLA

CVID Phenotypes Associated with Autoimmunity and Malignancy

• Low numbers of memory B cells – CD27+ CD21-, B220+, no class switch

• T cell activation, inverted CD4/CD8 • Multiple genetic phenotypes

– Example: TNFSR13B mutations (TACI) A181E

Rachid, Cur All & Asthma Report, 2006 Brandt, Autoimmune reviews, 2006

B cell differentiation Immature B cell

Mature Naïve B cell

BM

Immature B cell

Memory B cell

Plasma B cell

GC tissues

CD19 CD20 CD10 IgD/IgM+ CD27-

CD19/20 CD10 IgM+/IgD CD27- Not Class Switch

CD19/20 CD27+ IgM, IgG,A,E Class Switch

Y Y Y

Y

CD19/20neg CD38+

Classification of B cells subsets in CVID

• I. Impaired memory B cell differentiation – Ia- Highest risk for autoimmunity

• Low CD27, IgD/IgM switched B cells • Increased CD19high CD21lo

– Ib- Low switched memory B cells with normal CD19high CD21lo

• II. B cell subsets are normal

Warnatz et al, Blood, 2002

100 101 102 103 104

CD27

100

101

102

103

104

B22

0

49.7 12.6

34.13.54100 101 102 103 104

CD27

100

101

102

103

104

B22

0

80.9 5.67

7.076.34

Healthy Adult HIV-1

100 101 102 103 104

CD27

100

101

102

103

104

B22

0

96.8 0.49

0.0162.71

CVI

100 101 102 103 104

CD27

100

101

102

103

104

B22

0

5.14 0.31

93.51.06

B cell CLL

CD27

B22

0

Populations mixed: naïve (CD27-) memory (CD27+)

B cell subsets in Health and Disease

Loss of memory (CD27+) B cells

Accumulation of class switched homogneous Memory B cells

Treatment of Granulomatous Disease in CVID

• Optimize Gammaglobulin therapy • Corticosteroids • Immune modulation; cyclosporin,

hydroxychlorquine • Infliximab • ά CD20

Thatayatikom, JACI, 2005

CVID and Malignancy • Relative Risk for NHL

– 20 to 250 fold risk – EBV driven – MALT (low grade B cell lymphoma)

• Gastric carcinoma – 30X risk

• Colorectal carcinoma – 50X risk

Malignancy Associations Role of co-infection and inflammation

• 20% overlap with autoimmune manifestations of CVID

• Sprue and colorectal CA • Infections

– MALT- H pylori, chlamydia, borrelia, camplylobacter

– NHL- EBV, HHV8 Desar, Journal of Medicine, 2006

Management Options MALT

• Aggressive screening for H pylori by culture and biopsy – Serology NOT helpful

• Amoxicillin or Metronidazole • Frequent UGI and endoscopy for patients at risk

– Annual or bi-annual exams • Optimize IVIG • Anti-CD20 shown to be effective in early treatment

Monitoring the Non-infectious complications of CVID

• HIGH Degree of Clinical Suspicion

• Optimize the use of Gammaglobulin – Maintain high IVIG troughs >600 mg/dl

– Dosing 400-600 mg/kg

• Know the infectious co-morbidities – EBV, H pylori, HHV8, CMV, HCV, HepB

– Diagnosis based on antigen detection

Monitoring the Non-infectious complications of CVID

• Know the genetic co-morbidities – TACI,

• Aggressive use of imaging for at risk – HRCT at diagnosis

– UGI/ endoscopy for at risk

• Monitor for chronic immune activation – CRP, CBC, B and T cell flow cytometry

Use and interpretation of diagnostic

vaccination in primary immunodeficiency:

A working group report of the Basic and

Clinical Immunology Interest Section of the

American Academy of Allergy, Asthma &

Immunology

Journal of Allergy and Clinical Immunology September, 2012

Use of the pneumococcal polysacharide vaccine (PPV) in the evaluation of

humoral immune function • PPV responses vary greatly over time

among healthy subjects. • Post immunization titers should be

measured 4 to 8 weeks post immunization.

• PPV titers have been validated as measure of immune function. – Results of individual assay methods vary

Kamchaisatian, JACI, 2006

Pneumococcal Vaccination Responses

• Titers ≥ 1.3 g/mL are considered protective – Adequate pre-immunization titers do not require

addition immunizations to evaluate that particular serotype.

• Healthy subjects can mount a 2-fold rise above 1.3 g/mL

• > 4-fold rises when baseline titers >4.4 g/mL are rare.

• Booster PPV doses are unnecessary and not recommended as they promote vaccine hyporesponsiveness

Pneumococcal Vaccination

• Serotypes of 23 valent polysacharide vaccine: – 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14,

15B, 17F, 18C, 19A, 19F, 20, 22F, 23B, 33F – Serotypes in 13 valent conjugated pneumococcal

vaccine (6A) • Protective titers should be observed in at

least half the serotypes in a child and 2/3 in an adult to bee considered a normal response

Diagnosis of Specific Antibody Deficiency (SAD)

SAD diagnosis can be made if responses to PPV23 is deficient but responses to protein antigens (tetanus or diphtheria or conjugate vaccines) are intact with normal total Ig levels.

Orange, et al, JACI Sept, 2012

Diagnostic algorithm for children with recurrent bacterial sinopulmonary infections (OM, sinusitis, pneumonia)

Quantitative Immune Globulins IgG, IgA, IgM

Abnormal/low: Extend w/u for PIDD

Normal

IgG subclasses/Pre and post Immunization Titers Tetanus, Diptheria, Pneumococcal polysaccharide (PPS)

Dx: Specific Antibody Deficiency Normal IgG subclasses Decreased response to PPS*

IgG Levels are Related to IgG Dose

Trough IgG increases 121mg/dl for every 100mg/kg dose increase

Orange, et. al. Clin. Immunol. 2010 137:21-30

Inverse Correlation Between IVIg Levels and Infection1

Orange, et. al. Clin. Immunol. 2010 137:21-30

27% (Per 100mg/dL)

Black Box Warning

IVIG thrombosis risk • Why the black box warning?

– Activated Factor XIa found in all Ig products (WhinRho, HyperHepB, HyperRho)

– Estimated risk 0.84/1000 infusions – Risk greatest in:

• patients >45yr • Hypercoagulable states • Prior thrombotic events

Am J Hematol, 2013

Guidelines for IVIG infusions • Contraindicated in selective IgA deficiency.

– 40% of IgA deficiency have anti-IgA antibodies. • IgG half life ~ 28 days.

– Persists for up to 6 months. – Varies with subclasses (IgG3 shortest).

• Available as Subcutaneous or Intravenous preparations that vary from 5 to 20% concentration.

• Products vary in IgA, pH, osmolality, and stabilizer (amino acid or sugar),

What Patients should know before starting treatment with IVIG.

– IVIG is a derived from pooled human plasma in the United States all donors from U.S. plasma centers.

– Thrombosis and Renal Failure are the major AEs. – Products consist of primarily monomeric IgG, IgA and

IgM is removed, products vary with IgA content. – Most adverse effects are related to the amount of IgG

dimers in the product. – The products are generally thought to be pathogen free.

Nano-filtration results in >10 log depletion of potential blood-borne pathogens. No known transmission of HIV. Transmission of prion associated diseases is theoretical.

What Patients should know before starting treatment with IVIG.

• Efficacy: – on average patients treated with IVIG have < 1 Serious

bacterial infection/patient/year (FDA standard for efficacy), including sepsis, pneumonia, meningitis, and osteomyelitis.

– Efficacy in preventing sinusitis, otitis media, and gastroenteritis if not as great

IVIG Clinical Monitoring • Thrombosis in elderly, patients with

coagulopathies, or individuals receiving high doses.

• Safety labs: CBC and comprehensive metabolic panel.

• IgG levels every 3 to 4 months to maintain trough > 500mg/DL.

• Annual Hepatitis C antigen for patients at risk.

• The majority of Ig-related adverse events occur during: – A first infusion – During a change from one Ig product

to another1

• For this reason all such infusions should be performed under the highest level of supervision

1) Immune Deficiency Foundation, 2002 patient survey: http://www.primaryimmune.org/pid/survey.htm. Accessed April 8, 2006.

2) Gardulf A et al. Lancet. 1991;338:162-166.

When Do AEs Occur?

AAAAI Site of Care Guidelines

Global Differences in Use of SCIg

Advances in Theraputics, 2011

47 Berger M. Clin Immunol. 2004;112:1-7.

• Well tolerated by most patients • Ability to give large volumes per infusion allows

intermittent dosing (every 21–28 days)

• Requires venous access and trained personnel • IgG shifts in levels during dosing causes adverse

effects at or just after peak and during low troughs • Infrequent dosing may result in low troughs

Disadvantages

Advantages

IVIG Aministraion

48

SC Administration

Berger M. Clin Immunol. 2004;112:1-7.

Disadvantages

Advantages

• Well tolerated by most patients • Self infusion, venous access not required • Gradual absorption decreases rapid large swings in

serum IgG, reducing Aes associated with IVIg • Maintains more steady state consistent IgG levels • Requires frequent dosing due to relatively small

volume per infusion • Ability to self-infuse requires reliable and adherent

patient

Dosing and administration of SCIg • 137% of monthly IVIg dose divided into 4

weekly administrations. – 20% formulation is 151% of IVIG dose

• Subcutaneous sites; abdomen, thighs, flank, upper arms.

• Supplied as 10 and 20% solutions • 10% products administerd at 15 ml/ SC site • 20% products can be given at 25ml/ SC site.

Sample Calculation for Patient Receiving 20g IVIG/month

• For a 20% solutions of SCIG – 20g X 1.51= 30.2 grams IgG per month – As 20% solution total volume 150ml ÷4 weekly

infusions = 37.5 ml/week (round up or down to nearest vial size)

– Use 2 sites of 20 ml of SCIG

• For a 10% solution of SCIG – 20g X 1.37= 27.5 grams IgG per month

• As 10% solution total volume 275 ml ÷4 weekly infusions ≈ 75 ml/week

• Use 5 sites (15 ml of SCIG)

Adminisration of SCIG

SCIg Pharmacokinetics

SCIg Adverse Reactions

• 92% of patients have local injection site reactions – Decreases over time. – Primarily puritis, burning, and erythema.

• Contraindicated for patients with IgA antibodies or IgA associated anaphylaxis. – Decreases over time

Typical Injection site reaction

Immediate Post Infusion

2 hours Post Infusion

Key References • Practice Parameter for the diagnosis and management

of primary immune deficiency, Annals of Allergy, Asthma, & Immunology 94: S1, (2005)

• Salzer, et al, Common Variable Immunodeficiency: the power of co-stimulation, Seminars in Immunology, 18: 337 (2006)

• Castigli, et al, TACI is mutant in common variable immunodeficiency and IgA deficiency, Nature Genetics, 37:829 (2005)

• Rachid, et al, TACI mutation in CVID and IgA deficiency, Current Allergy and Asthma Reports, 6:257 (2006)

Key References • Cunningham-Rundles, et al, Common variable

immunodeficiency: clinical and immunological features, Clinical Immunology 92: 34 (1999)

• Busse, et al, Pulmonary Complications of common variable immunodeficiency, Annals of Allergy, Asthma, & Immunology, 98: 1 (2007)

• Wang, et al, Treatment and outcome of autoimmune hematologic disease in CVID, Journal of Autoimmunity 25:57 (2005)

• Morimoto, and Routes Granulomatous Disease in Common Variable Immunodeficiency, Current Allergy and Asthma, Report, 5: 370 (2005)

Key References

• Thatayatikom, et al, Infliximab treatment for severe granulomatous disease in common variable immunodeficiency, Annals of Allergy, Asthma, & Immunology, 95: 293 (2005)

• Desar, et al, Extranodal marginal zone

(MALT) lymphoma in common variable immunodeficiency, 64: 136 (2006)