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

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 Ad boards on asthma, immunodeficiency AstraZeneca, CSL Behring, Sanofi Speakers bureau member Talks on asthma, urticaria, atopic dermatitis AstraZeneca, Novartis, Sanofi Payment from a commercial organization. (including gifts or other consideration or ‘in kind’ compensation) Grant(s) or an honorarium Honorarium for CPD work CSACI 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- 2 nd or 3 rd decade

Prevalence PID Complement, Phagocytic, Cellular , 14% 2% 17% Combined, Humoral, 23% 44% • >300 different defects described thus far ▫ Causative genes known in ~80%

Predominantly antibody deficiencies Selective IgA deficiency 6

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 Recurrent sinopulmonary infections with early components encapsulated bacteria terminal components Recurrent Neisseria infections

B cell immunodeficiencies  Heterogenous group of disorders that share marked reduction or absence of serum immunoglobulins 1  Account for 65% of all PIDs 2  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% of 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 syndrome 1  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 age 1  Adults IgG3  Children IgG2 2  Other d/o: ataxia-telengiectasia and IgA deficiency 3 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/L 1 (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 Yes No required? 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 Saves patient: approximately $1000–$1500 annually Hospital: Nursing hours, equipment Saves government: approximately $2000–$2600 annually AE, adverse event 1. Adapted from Lachance, et al., Curr Oncol, 2016; Feb;23(1):42-51

SCIG effective for immunodeficient patients: evidence-based review (2013)  25 studies assessed: 19=PID; 1=SID; and 5=health economic studies — IgG increase after dose-equivalent switch IgG (g/L) Higher trough levels with SCIG given at the same dose as IVIG over a given period A1-7, individual studies Size of circles reflects number of patients included Lingman-Framme and Fasth, Drugs, 2013; 73:1307-1319.

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