Goals of this presentation: 1.Prevent morbidity and mortality due to the failure to recognize Primary Immunodeficiency 2. Decrease your risk of having to answer the question: “Why did you miss this?” 3. Review the safe and effective use of gamma globulin Presentation by: Richard L. Wasserman, M.D.,Ph.D. Clinical Professor of Pediatrics University of Texas Southwestern Medical School

1. Recognition and Treatment of Primary
Immunodeficiency in Adults
Richard L. Wasserman, M.D.,Ph.D.
Clinical Professor of Pediatrics
University of Texas Southwestern
Medical School

2. Disclosures
• Investigator – Baxter Healthcare, CSL
Behring, Korean Green Cross
• Consultant – Baxter Healthcare, Cangene,
CSL Behring, Grifols, Kedrion
• Speaker – Baxter Healthcare, CSL Behring

3. Goals of this Presentation
• Prevent morbidity and mortality due to the failure to
recognize Primary Immunodeficiency
• Decrease your risk of having to answer the question:
“Why did you miss this?”
• Review the safe and effective use of gamma globulin

4. Primary Care Doctors and PIDD’s
Specialty % with PID Patients
General Practice 10%
Family Practice 10%
OB/GYN 12%
Internal Medicine 9%
Pediatrics 20%
Note that mortality from PID prior to age 20 is low. Pediatricians have more PID patients because they
think about the diagnosis. RLW comment.
National Survey of Genetic Issues, National Center for Genome Resources

5. Conditions Before Diagnosis
Arthritis
Bronchitis
Cancer
Otitis
Diarrhea
Hepatitis
Meningitis
Pneumonia
Sepsis
Sinusitis
0% 10% 20% 30% 40% 50% 60% 70%
Immune Deficiency Foundation Survey

6. Hospitalizations before Diagnosis
17%
32%
None
10%
30%
5%
21+
6%
One
2-5
6-10
11-20
Immune Deficiency Foundation Survey

7. Age at Diagnosis of PID
Less than 1
2-5
6-11
12-17
40-64
18-39
0% 10% 20% 30%
Percent of patients
65+
Age
Immune Deficiency Foundation Survey

8. Time to Diagnosis - CVID
• Median age of onset of symptoms, 23 for
males and 28 for females
• Mean age for diagnosis of CVID, 29 for males
and 33 for females
• In this study, there was at least a 5 year delay
from the onset of symptoms to the diagnosis
Cunningham-Rundles, C, Bodian, C. Clin. Immunol. 1999.

9. 10 Warning Signs*
• 8 or more new ear infections
in 1 year
• 2 or more serious sinus
infections in 1 year
• 2 or more months on
antibiotics without benefit
• 2 or more pneumonias in
on year
• Failure of an infant to gain
weight or grow normally
• Recurrent, deep skin or
organ abscesses
• Persistent thrush after 1 year
of age
• Need for intravenous
antibiotics
• 2 or more deep-seated
infections
• A family history of Primary
Immunodeficiency
* “Ten Warning Signs” is a project of the Jeffrey Modell Foundation.

10. Effect of PID Diagnosis on
Hospital Admissions
14%
21%
8%
5% 4%
48%
17%
32%
10%
30%
5%
6%
Before After
One 2-5 6-10 11-20 21+ none
Hospital Admissions
Immune Deficiency Foundation Survey

11. Host Defense
• Barriers to infection
– Organ - burn, tracheo-esophageal fistula
– Cell - cilia dysmotility syndrome
– Organelle - cystic fibrosis
• Adaptive immunity
– Humoral and cellular immunity
• Inate immunity
– Phagocytes and complement

12. Immunodeficiencies
Antibody Deficiency
Combined
Immunodeficiency
Cellular Deficiency
Neutrophil Dysfunction
Complement Deficiency
Other
78%
Immune Deficiency Foundation Survey

13. Immunoglobulin Wall of Defense
IgG1 IgG2 IgG3 IgG4
Anti-polio
Anti-tetanus Anti-
S. pneumo

14. Bruton’s Agammaglobulinemia
IgG1 IgG2 IgG3 IgG4

15. Common Variable Immunodeficiency
IgG1 IgG2 IgG3 IgG4

16. Antibody Deficiency
IgG1 IgG2 IgG3 IgG4

17. Humoral Immunodeficiency
• Problems primarily with extracellular
pathogens (eg: pyogenic cocci, H. influenza,
M. catarrhalis)
• Common organisms and infections with an
uncommon frequency and severity
• Sinopulmonary, gastrointestinal and
cutaneous infections are most common

18. Goals of an Immunologic Evaluation
• Prevent premature mortality
• Minimize physical morbidity
• Maximize the potential for normal physical
and psychosocial growth and development
• Define the basis of abnormal infection
susceptibility to optimize treatment

19. Sinopulmonary Infections Indicating a
Workup
• Recurrent or persistent otorrhea after tubes
• Recurrent otitis despite antibiotic prophylaxis
• Recurrent sinusitis after two surgeries
• Two or more bacterial pneumonias clustered in
time
• Persistent interstitial pneumonitis
• A combination of the above

20. Sinopulmonary Presentations
• 21-year-old
• 3 yr history of recurrent
pneumonia and recent
weight loss
• No prior history of
infections
• Common Variable
Immunodeficiency

21. Chronic Sinusitis and Immunodeficiency
Number of Patients
Age
Diagnoses
Selective IgA Deficiency
CVID
IgG Subclass Deficiency only
Antibody Deficiency only
IgG Subclass + Antibody Deficiency
23
27-51
21/23
2/23
4/23
1/23
5/23
9/23
Manning SC, Wasserman RL, Leach J, Truelson J, Am J Rhinology, 1994

22. GI Presentations in All Age Groups
• Presentations
– Chronic diarrhea especially
with a persistently positive
viral isolation
– Recurrent Giardia or other
enteric parasite
– Idiopathic malabsorption
• Susceptibility factors
– Cystic fibrosis
– Cellular
immunodeficiency
– Antibody production
defect

23. Soft Tissue Infections
Indicating a Workup
• Two or more abscesses w/o an obvious cause
• Two or more episodes of adenitis w/o an
obvious cause
• Liver abscess
• Wound infection unresponsive to appropriate
therapy
• Periodontal disease in a pre-teenager

24. Deep Tissue Infections
Indicating a Workup
• Two or more episodes of
– Meningitis
– Septic arthritis
– Osteomyelitis
• One or more episodes of the above
infections plus sinopulmonary infections

25. “Infection” Non-Problems
• Recurrent viral upper respiratory tract
infections – colds
• Recurrent tonsillitis or pharyngitis – Strep
throat or viral
• Wheezy bronchitis or pneumonia – asthma
• Chronic rhinitis – allergy or non-allergic
rhinitis

26. Humoral Immunodeficiency Workup
• Antibody production defects
– Quantitate Ig isotypes – IgA, IgG, IgM
• IgG subclasses – limited value
• Not IgD
• IgE is helpful
– Measure specific antibody production
• Protein (diphtheria/tetanus) antigens
• carbohydrate (pneumococcal polysacharide) antigens

27. Do the Complete Work up!
• 72 yo with recurrent pneumonia (two to three per
year for several years)
• IgA, IgG, IgM normal
– Pneumovax non-responder
– Diagnosis – antibody deficiency
• Treated with IGIV – no pneumonias for 12 years
• Age 84 IgA and IgM are undetectable
– CVID

28. Goals of IgG Therapy
• Decrease the frequency and severity of infections
• Minimize the risk of major adverse events due to IVIG
• Diminish the frequency and severity of minor infusion
related side effects
• Improve patient satisfaction with IVIG therapy

29. Relation of IgG Dose to Trough Level
Trough IgG increases 121 mg/dL for every 100mg/kg dose increase
Orange et al. Clin Immunol. 2010. .

30. IgG Trough Level Is Inversely Correlated
To Pneumonia Incidence
Every 100mg/kg trough level increase decreases
pneumonia incidence by 27%
Orange, et. al. Clin. Immunol. May 2010, 137:21-30

31. The IgG Level That Protects Against Recurrent Infection
Is The Biologic IgG Level
The correct dose of gamma globulin is
the dose that keeps the patient well.
Bonagura VR et al. J Allergy Clin Immunol. 2008.

32. Modalities of IgG Delivery
• Intramuscular
– Painful, no longer use
• Intravenous
– Infrequent dosing, major and minor side effects
• Subcutaneous
– Frequent dosing, fewer side effects than IV
• Enzyme facilitated subcutaneous
– Infrequent dosing, fewer side effects than IV

33. Safety Is the First Priority
• Patients are most concerned about infection risk
• In 2012, all gamma globulin products commercially
available in North America appear to be free of
blood borne pathogens
• Concern about infection has driven manufacturers
to create products that are “safer than safe”

34. Viral Inactivation Methods – At Least Three
• Inactivation steps
– Cohn-Oncley fractionation
– S/D
– Heat treatment
– Freeze-drying
– Photoinactivation (UVC)
– Enzymatic treatment
– Low pH incubation
– Caprylate
• Removal steps
– Precipitation
– Depth/cloth/nanofiltration
– Chromatography

35. “Rate-Related” Side Effects
Occur in about 20% of PIDD patients.
• Chills
• Headache
• Fever
• Cough
• Flushing
• Chest pain
• Sinus tenderness
• Hypertension
• Hypotension
• Abdominal pain
• Nausea
• Vomiting
• Diarrhea

36. Serious IGIV Adverse Events/Risk Factors
• Thromboembolic events – MI, Stroke
– Age, previous thrombosis, IgG dose/rate
• Aseptic meningitis
– History of migraine
• Renal failure
– Age, diabetes, renal compromise, carbohydrate
stabilized (particularly sucrose) IgG

37. Summary of IgG Side Effects
• Serious adverse events are relatively rare
• Minor side effects are common with IGIV
• The risk of both minor and serious adverse events can
be decreased by subcutaneous administration
• Often, assessing risk and individualizing drug choice
and route can prevent serious adverse events

38. Technical Aspects of IGSC Therapy
• Standard “in-label” procedures are often modified by
experienced immunologists to minimize side effects and
optimize the patient experience
• Initiation of therapy – transition from IV vs initial
therapeutic approach
• Infusion sites – number, selection and volume per site
• Needles, pumps
• Infusion rates
• Infusion interval – daily, weekly, biweekly

39. Commonly Used IGSC Sites

40. IgG Replacement: IGIV vs IGSC

41. Enzyme-Facilitated IGSC – IGHy
• Hyaluronidase
– Digests hyaluronan, the major constituent of the
subcutaneous space
– Enhances bulk fluid flow
• Enables rapid infusion of high dose IgG into the
subcutaneous space

42. Mechanism of Action of Hyaluronidase
·Focal depolymerization of hyaluronan increases rates of
infusion/injection
·Increased dispersion decreases residence time in the interstitium
·More rapid uptake leads to better pharmacokinetics resulting in
increased bioavailability
·Because of the of short enzyme half-life and rapid endogenous
substrate turnover in the skin, the change is rapidly reversed

43. IGSC vs IGHy Infusion
IGSC site 15ml

44. IGHy – IgG + Human Hyaluronidase*
• Enzyme facilitated subcutaneous IgG infusion
– Human recombinant hyaluronidase is infused
subcutaneously
– The subcutaneous needle hub is then connected to an IgG
reservoir
– IgG is infused
• Rate up to 300 mL/hr
• Volume up to 600 mL/site
*At this time, the US FDA is evaluating a Biologicals Licensing Application for hyaluronidase-facilitated
subcutaneous infusion of IgG. It is not approved for use in the US.

45. Case Presentation 1
• 24-year-old female with CVID
– IGIV therapy for 14 years
– Current dose 575 mg/kg/mo
– Recent IgA 41 mg/dL, IgG 997 mg/dL, IgM 17 mg/dL
• Complains of malaise and fatigue
– Decreased intellectual function before infusion
– Begins 5 days before infusion, resolves day after infusion
– Six episodes of antibiotic-responsive purulent rhinorrhea in
the past 12 months

46. Case Presentation 2
• 32-year-old male CVID patient treated with IGIV
for 6 years
• Systemic side effects
– Debilitating migraines begin 6 hours after infusion
for the past 6 months
– Pre-medications (steroids, NSAIDs, antihistamines)
provide limited benefit
– No difference with 3 different products
• Alternatives in treatment

47. Case Presentation 3
• 18-year-old XLA patient has done well on IGIV
for 16 years.
– Requires treatment antibiotics less than once a year
– No problems with IV access or IgG side effects
• Leaves to attend college out of town
– Therapeutic alternatives

48. Primary Immunodeficiency
• A family of disorders (>200) characterized by an
increased risk of infection
• 50% of patients are diagnosed as adults
• Effective treatment is available for most patients
• Early diagnosis and treatment have a dramatic effect
on quality of life and may be life saving.

49. IgG Replacement Therapy
• The ideal IgG dose, route of administration, and dosing
interval is individual to the patient
• The correct IgG dose is the dose that keeps the patient
well
• IGIV allows infrequent dosing but results in significant
variations in IgG level between infusions
• IGSC may be given from daily to every 14 days
enhancing patient control and maybe adherence
• For some patients, IGHY may represent the advantages
of both IV and SC administration

51. Recognition and Treatment of Primary
Immunodeficiency in Adults
Richard L. Wasserman, M.D.,Ph.D.
Clinical Professor of Pediatrics
University of Texas Southwestern
Medical School