This presentation is about chronic infections in patients and earlier diagnosis of immunodeficiency. The goals of the presentation are: 1. Understand the role of innate and adaptive immune systems in the defense against infection 2. Recognize the common presentations of common primary immunodeficiencies 3. Be able to identify patients in an ENT practice that may have a primary immunodeficiency Presentation by: Dr. Richard L. Wasserman and Dr. Scott Manning

1. Intractable Sinusitis and Other
Conundrums
Richard L. Wasserman, M.D.,Ph.D.
Clinical Professor of Pediatrics
University of Texas Southwestern
Medical School
Scott Manning, M.D.
Professor of Otolaryngology
University of Washington
School of Medicine

2. Relevant Disclosures
• Investigator – ADMA, Alcon, Baxter, Biotest,
CSL Behring, GSK, Kedrion, Merck, USDA
• Consultant - ADMA, Baxter, CSL Behring,
Kedrion
• Speaker – Alcon, Baxter, CSL Behring, GSK

3. Goals of this Presentation
• Prevent morbidity and premature mortality
due to the failure to recognize Primary
Immunodeficiency
• Decrease your risk of having to answer the
question: “Why did you miss this?”
• Enhance your ability to provide better
care to your patients

4. Learning Objectives
• Understand the role of innate and adaptive
immune systems in the defense against
infection
• Recognize the common presentations of
common primary immunodeficiencies
• Be able to identify patients in an ENT practice
that may have a primary immunodeficiency

5. Case 1 Patient WJ
• Frequent otitis media through age 5
– Multiple episodes beginng at 9 months of age
– Myringotomy tubes X 2, adenoidectomy
– Otitis continues as a problem at age 5
• No other identified infections
• Monoarticular JRA at age 2

6. Audience Response
• Why is he having so many episodes of otitis?
– Allergy
– Non-allergic rhinitis
– Primary immunodeficiency
– Gastroesophageal reflux
– Congenital midface structural defect

7. Recurrent Otitis Patient WJ
• New pediatrician at age 5
• Laboratory evaluation
• IgA <5mg/dL, IgG 25mg/dL, IgM 11mg/dL
• Bruton’s Disease

9. Incidence
• Use slide from Gammagard SC first deck

10. 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

11. Antibody Production Defects

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

13. Bruton’s Agammaglobulinemia
IgG1 IgG2 IgG3 IgG4

14. Bruton’s Agammaglobulinemia
• X-linked
• Defect in Bruton’s Tyrosine Kinase (BTK) which
is required for B cell differentiation
• The is no specific antibody production
• Some patients produce “junk”
immunoglobulin

15. Common Variable
Immunodeficiency
IgG1 IgG2 IgG3 IgG4

16. Common Variable Immunodeficiency
• Defective antibody and immunoglobulin
production
• Low immunoglobulin concentrations
• A heterogeneous group of disorders of B cells,
T cells and B-T interaction

17. Antibody Deficiency
IgG1 IgG2 IgG3 IgG4

18. Antibody Deficiency
• Immunoglobulin class and subclass
concentrations are normal
• Specific non-responsiveness to particular
antigens
• Defective response to bacterial polysaccharide
antigens is the most common defect

19. 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

20. Cellular Immunodeficiency

21. DiGeorge Syndrome
• Thymic dysplasia,
hypoparathyroidism, cardiac
anomalies
• Other anomalies as well:
craniofacial, renal, etc.facial
features
• Though primarily a T cell
defect, there is abnormal T
cell modulation of B cell
function
• Frequently a partial defect of
immunity

22. Severe Combined Immunodeficiency
• Complete or nearly complete absence of B
and T cell function
• Many different genotypes result in similar
clinical phenotypes
• The most common form is an X-linked defect
in the IL2 receptor gamma chain
• Infection with common and uncommon
pathogens

23. Combined Immunodeficiencies, other
• Wiskott-Aldrich Syndrome - eczema,
thrombocytopenia and progressive
immunodeficiency, particularly otitis in infants
• Ataxia-Telangectasia - neurologic disorder
with telangectasia formation early and
progressive immunodeficiency

24. Cellular Immunodeficiency
• Patients have problems with viral, fungal and
parasitic infections.
• These patients are subject to unusual and
opportunistic infections.
• At this time, adenosine deaminase (for ADA
deficiency SCID) and stem cell transplant are
the only therapies.

25. Phagocytic Cell Defects

26. Phagocytic Cell Defects
• Neutropenia
– Chronic
– Cyclic
• Functional Disorders
– Chronic Granulomatous Disease
– Leukocyte Adhesion Deficiency

27. Chronic Granulomatous Disease
• X-linked or autosomal recessive inheritance
• Inability to generate a respiratory burst (eg:
H2O2 production) following a stimulus
• Chemotaxis (cell movement) and phagocytosis
are normal

28. Leukocyte Adhesion Deficiency
• Autosomal recessive defect in cell adhesion
proteins
• Defective ICAM ligand
• Cell movement (chemotaxis) and phagocytosis
are abnormal

29. Photo Slide

30. Phagocytic Cell Defects
• Bacterial and fungal infections, Aspergillus
infection is the most common cause of death
• Superficial and deep tissue abscesses
• Osteomyelitis and liver abscess are more
common
• Organisms of low pathogenicity – uncommon
gram negative rods
• Periodontal disease

31. Complement Deficiency

32. Complement Deficiency
• Any component may be missing or inactive
• Recurrent invasive bacterial infections
• The absence of C3 is the most severe
• The absence of C5-9 is associated with
recurrent Neisserial disease

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

34. Case 2 Recurrent Sinusitis after
Surgery x 2

35. Audience Response
• Chronic sinusitis

36. 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

37. Audience Response
• 28 year old female with recurrent sinusitis
after functional endoscopic sinus surgery.
What is the most appropriate next step?
– Revision surgery
– Chronic oral antibiotic therapy
– Daily aerosolized antibiotic therapy
– Cilia biopsy
– Allergy testing
– Immunodeficiency evaluation

38. 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.

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

40. PID Is Not Just a Pediatric
Diagnosis
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

41. 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.

42. 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

43. Susceptibility of Recurrent
Sinusitis/Otitis
• Allergy
• Non allergic rhinitis
• Daycare/school teacher’s exposure
• ??
• PI

44. ENT presentations of PID
• Chronic and recurrent infection
– Otitis
– Sinusitis
– Parotitis/Sialitis
– Adenitis
• Unexpected organisms
• Physical Exam – may be evidence of active
infection or past otitis

45. Diagnostic Studies
• Imaging?
• Allergy testing
• Immunologic testing
– Quantitative Immunoglobulins
– Specific antibody production
– Cell mediated immune function
– Phagocytic cell function

46. 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

47. Rara Avis
• Case 3
• Frequent otitis media and purulent rhinitis
during the first two years of life
• H. influenza epiglotitis at age two
• Vaccine preventable disease
• Bruton’s Disease

48. 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

49. 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

50. Treating PIDD Patients
The Immunodeficiency
• Hematopoetic Stem Cell
Transplant (HSCT) for
Combined Immunodeficiency
and Neutrophil defects
• Prophylactic antimicrobials
• Gamma globulin for antibody
deficiency
The Infections
• Aggressively search for the
pathogen
• Culture guided therapy
whenever possible
• Higher doses than normals
under some circumstances
• Longer duration of therapy than
normals, always

51. Management of PID

52. Role of ENT in PI management
• Management of difficult otitis, sinusitis
– Local care of the middle ear or sinuses
• Cultures are especially important in soft tissue
infections
– At least 48 hours off antibiotics
– Culture for “everything” – ID is often helpful to work with
the lab and follow results
– Slow growing organisms
• Surgery
– Benefits are often short-lived

53. IgG Therapy
• What is gamma globulin
– Plasma source
– Plasma processing
• Routes of gamma globulin administration
– IGIV
– IGSC

54. Two Physician’s Children
Patient AP Patient WJ
• Frequent otitis media
and purulent rhinitis
during the first two
years of life
• H. influenza meningitis
at age two
• Bruton’s Disease
• Frequent otitis media
through age 5
• No other identified
infections
• Monoarticular JRA at age
2
• New pediatrician at age 5
• Bruton’s Disease

55. Contact Information
• Dallas Allergy Immunology
• www.dallasallergy.net
• 972.566.7788
• info@dallasallergy.net