Immunodeficiency 101 for the Internist Lori Connors, MD, MEd, FRCPC - - PowerPoint PPT Presentation

Canadian Society of Internal Medicine

Annual Meeting 2019

Halifax, NS

Immunodeficiency 101 for the Internist

Lori Connors, MD, MEd, FRCPC

Dalhousie University

CSIM Annual Meeting 2019

Lori Connors: Immunodeficiency for the internist – October 3, 2019

The following presentation represents the views of the speaker at the time of the presentation. This information is meant for educational purposes, and should not replace other sources

• f information or your medical judgment.

Learning Objectives:

By the end of this session participants will be able to:

• List warning signs of immunodeficiency
• Distinguish between primary and secondary immunodeficiency
• Describe common adult presentations of immunodeficiency
• Explain appropriate work-up and treatment of humoral immunodeficiency

CSIM Annual Meeting 2019

Conflict Disclosures

Definition: A Conflict of Interest may occur in situations where the personal and professional interests of individuals may have actual, potential or apparent influence over their judgment and actions.

I have the following conflicts to declare

Company/Organization Details Advisory Board or equivalent

AstraZeneca, CSL Behring, Sanofi

Ad boards on asthma, immunodeficiency

Speakers bureau member

AstraZeneca, Novartis, Sanofi

Talks on asthma, urticaria, atopic dermatitis

Payment from a commercial organization. (including gifts or other consideration or ‘in kind’ compensation) Grant(s) or an honorarium

CSACI

Honorarium for CPD work

Patent for a product referred to or marketed by a commercial organization. Investments in a pharmaceutical organization, medical devices company or communications firm. Participating or participated in a clinical trial

Primary Immunodeficiency

 Immune defect that results from genetic

defect

 Incidence 1 in 2000 live births  Presentation variable

 Neonatal onset  6 months of age (once maternal antibodies

decline)

 Milder forms- 2nd or 3rd decade

Prevalence PID

Complement, 2% Cellular , 14% Humoral, 44% Combined, 23% Phagocytic, 17%

• >300 different defects described thus far

▫ Causative genes known in ~80%

Predominantly antibody deficiencies

6

Selective IgA deficiency

Classification of Primary Immunodeficiencies

 2017 IUIS (International Union of

Immunological Societies) phenotypic classification

 Now renamed Inborn Errors of Immunity

Bousfiha, A., Jeddane, L., Picard, C. et al. J Clin Immunol (2018) 38: 129. https://doi.org/10.1007/s10875-017-0465-8

Bousfiha, A., Jeddane, L., Picard, C. et al. J Clin Immunol (2018) 38: 129. https://doi.org/10.1007/s10875-017-0465-8

http://www.info4pi.org

Infections as presentation of PIDs – in a very simplified way

Category of Disorder Typical Infectious History Cellular immune defect Recurrent opportunistic infections Humoral immune defect Recurrent sinopulmonary infections with encapsulated bacteria Neutrophil defect Recurrent bacterial and fungal infections involving the skin and organs IFN-gamma/IL-12 pathway defect Recurrent atypical mycobacterial (includes BCG), Salmonella infections Complement defects early components Recurrent sinopulmonary infections with encapsulated bacteria terminal components Recurrent Neisseria infections

B cell immunodeficiencies

 Heterogenous group of disorders that share

marked reduction or absence of serum immunoglobulins1

 Account for 65% of all PIDs2  Combined T and B cell disorders

1. Annu Rev Immunol 2009, 27:199-227 2. Lancet 2008;372:489-502

Common Variable Immunodeficiency

 Low IgG and either low IgA or IgM  Incidence ~1 in 50,000  2 peaks for presentation 5-10yo, 20-30yo  Present with recurrent sinopulmonary

infections

 + FHx in ~10%

Bonilla et al. AAAAI Practice Parameter on PID. JACI 2015;136(5)

Salzer et al. Seminars Immunol. 2006;18(6):337-46.

Park, M. CVID Lancet 2008

Autoimmunity in up to 35%

• f pts

In 20-25% of CVID pts. autoimmune disease precedes infections, so screening IgG, IgA, IgM in autoimmune w/u warranted to exclude CVID. These pts. esp. have increased lymphoma risk as well.

Agarwal & Cunningham-Rundles 2009

Good syndrome1

 CVID with thymoma  Adult-onset (avg age 56 yrs)  Associated with more opportunistic infections  Autoimmune diseases: pure red cell aplasia

and neutropenia

 Chronic diarrhea of unknown origin

• 1. AAAAI practice guideline 2015

IgG subclass deficiency

 First described in 60’s and 70’s  Defined as serum IgG subclasses more than

2 SDs below normal mean for age1

 Adults IgG3  Children IgG22  Other d/o: ataxia-telengiectasia and IgA

deficiency3

1. JACI 2002;109:581-91. 2. Int Arch Allergy Appl Immunol 1987;82:476-80. 3. Monogr Allergy 1986;20:171-8

Management

 IVIG or SCIG

 400-600 mg/kg ideal body weight  Given q28days (weekly if SCIG)  Aim trough IgG > 7 g/L1 (ideally 7.5-8.5g/L)

 Treat autoimmune diseases 2  Good syndrome: remove thymoma

• 1. Roifman, 1985
• 2. AAAAI practice guideline 2015

AE’s IVIG

Wasserman, JACI Pract 2016

SCIG

 Cuvitru (Hizentra, Cutaquig)

 1:1 dosing with IVIG, given on weekly basis  Push or pump methods

 Advantages

 Home administration  More steady state levels  Less serious side effects (more local reactions)

Canadian Perspective – Advantages of SCIG vs IVIG

Variable Intravenous Subcutaneous

Administration Once every 3–4 weeks by nurse in hospital Flexible: daily, weekly or biweekly; administered by patient at home and when travelling Efficacy Reduces frequency and severity of serious bacterial infections equally Venous access required? Yes No Nursing required? Yes, to administer in medical facility Yes, for initial training of patient Systemic AEs? More common Infrequent Local AEs Infrequent Expected and mild Training required? No special skill required by patient or family Requires training of patient or family, good dexterity, good vision, capacity to learn new technique Costs Patient: Loss of work, travel, parking Hospital: Nursing hours, equipment Saves patient: approximately $1000–$1500 annually Saves government: approximately $2000–$2600 annually

• 1. Adapted from Lachance, et al., Curr Oncol, 2016; Feb;23(1):42-51

AE, adverse event

SCIG effective for immunodeficient patients: evidence-based review (2013)

 25 studies assessed:

—

19=PID; 1=SID; and 5=health economic studies

Lingman-Framme and Fasth, Drugs, 2013; 73:1307-1319.

Higher trough levels with SCIG given at the same dose as IVIG

• ver a given period

IgG (g/L)

A1-7, individual studies Size of circles reflects number of patients included

IgG increase after dose-equivalent switch

Secondary Immunodeficiency

www.esid.org

Case 1

 52 year-old female referred to Immunology by

Respirology, seen in outpatient clinic

 Admitted to CTU 3 times over 2 year period  Admission diagnoses:

 Pneumonia  Empyema  Pleural effusion

Case 1

 Admissions all took place in winter months,

always after a cruise “down South”

 Did not require ICU/IMCU  Treated with IV abx, O2  Pleurocentesis done during empyema

admission- “frank pus”

Some Questions…

 What would you ask on history?  Expected physical exam findings?  What work-up would you do?  What’s your differential?

Labs

 Initial immunoglobulin levels

 IgG Undetectable (6.50-15.20g/L)  IgA Undetectable (0.95-3.59g/L)  IgM Undetectable (0.46-3.04g/L)

What’s the Diagnosis?

 What further work up needs to be done?  What are your treatment recommendations?

http://www.info4pi.org

http://www.info4pi.org

Case 1 Results

 Vaccine responses:

 Measles Non-immune  Varicella Non-immune  Tetanus titre <0.01 IU/mL  Pneumococcal titre: 50

 CD19 numbers slightly low  Repeat IgG now 1g/L

Case 1

 Dx of CVID made  Patient started on IVIG q28 days  Transitioned to SCIG  No bacterial infections since

Monitoring

 Seen in outpatient clinic q3-6 months and

prn

 Monitor for infections, low threshold for

antibiotics

 Surveillance with PFTs/ CT chest q2years  Monitor for any side effect from IVIG, viral

transmission (liver enzymes/function, viral hepatitis screen done yearly)

Case 2

 50yo male admitted to CTU with pneumonia  Arrives to floor and looks ++ SOB, crackles

and wheezes throughout

 BP 80/50 HR 120 reg  Febrile T 39.5 RR 40 sats 90% on 5L O2

Chart review

 PMHx:

 Mod severe mitral stenosis  CLL with chemo completed 6 months prior

 Admitted for pneumonia twice in last few

months

 One admission required ICU, IMCU, BiPAP

and pressors (+CHF)

 Prior to 1 yr ago, no Hx infections

Chart review

 Had Ig’s checked during last 2 admissions

 Normal IgA, IgM  IgG 1-2g/L  Lymphocyte count low 0.65

Case 2

 Diagnosed with secondary

immunodeficiency, given Hx CLL

 Treatment initiated with IVIG q28 days  No infections or admissions since  Patient describes quality of life 1000%

improved since starting treatment

Causes of infection in patients with CLL1:

• 1. Friman, Hematol Oncol, 2016; 34: 121-132; 2. Lachance, et al., Curr Oncol, 2016; Feb;23(1):42-51; 3. Papanicolaou G and Mehta J.

Chapter 3 in Principles and Practice of Cancer Infectious Diseases. ed. Safdar A. Springer; 2010

• In CLL, an intrinsic defect in the clonal B-cells leads to unbalanced

immunoglobulin chain synthesis resulting in hypogammaglobulinemia3

• In CLL, HGG is progressive, typically worsening as the disease evolves1

Multifactorial pathogenesis of immunodeficiency in CLL

Infection in CLL patients Anti-CD20 antibody treatment Alkylating agents Purine analogs Dysfunctional T-helper cells prevent normal antibody response Hypogammaglobulinemia

Canadian Perspective – Algorithm for IgRT in CLL

• 1. Lachance, et al., Curr Oncol, 2016; Feb;23(1):42-51

a Where a patient has “normal” levels of

IgG, but a phenotype consistent with humoral immunodeficiency, the patient should be evaluated for monoclonal gammopathy.

b Response to vaccination before and

after boost. For example, for tetanus,

• btain serum for a pre-vaccine titer, then

administer the vaccine (same day), and 4 weeks later, measure the response to boost.

Case 3

 45yo female admitted to CTU with CAP  Requires supplemental O2, CXR shows LLL

and RUL pneumonia

 Sputum- Strep pneumo  3rd pneumonia in 6 months  IgG, IgA, IgM normal

Case 3

 IgG1, 3, and 4 all low  Tetanus titre <0.1 IU/mL  Vaccinated with Tdap and titres checked 4

weeks post

 Tetanus titre <0.1IU/mL

 Started on SCIG and no further admissions,

antibiotics