1. Primary Immunodeficiency Syndromes

2. Welcome to the module on Primary Immunodeficiency Syndromes
Please take this brief pre-module quiz

3. Case 1
63 year old man presents with failure to thrive, dysphagia, diarrhea, cough, and SOB
He was in his USOH until 6 weeks prior, when he developed watery diarrhea 4-7x/day
Cough and SOB in the last few days
Saw his PCP, negative C dif, tried Cipro/azithro, immodium, and probiotics, without improvement
Now he is presenting to the ED febrile, ill-appearing, and profoundly SOB

4. Past Medical History Thymoma:
Initially diagnosed in late 1980’s, when he developed Myasthenia Gravis (ptosis). He initially had local disease treated w/ resection
1990’s: local recurrence with lung invasion (stage 3 disease), received surgery, chemotherapy, radiation
2000’s: residual disease burden remains, but fairly inactive and he was followed by Hematology-Oncology until 12/2013 (his Dr retired)

5. CT scan 2016
Assessment of the mediastinum reveals para-aortic soft tissue area, 38 x 25
mm, slightly bigger than on the prior study (34 x 18 mm when compared to 22
December 2011 the changes in more pronounced (29 x 18 mm and)
Multiple pleural nodularity as are present,
involving the entire left pleura

6. Candida esophagitis
Upper Endoscopy
Candida esophagitis

7. Colonoscopy
CMV colitis
Diffuse ulcerations on colonoscopy

8. Pneumocystis carinii pneumonia

9. Also found to have giardia via stool DFA, and Salmonella bacteremia
HIV (3rd gen assay and viral load) negative
WBC 4.2, with normal differential (no neutropenia or lymphopenia)

10. Infectious Disease consult
“Please help us sort out treatment plan”
“…and figure out if he is immunosuppressed, and if so why”
“…and what prophylaxis he should be on”
“…Thanks!”

11. Overview of Immunodeficiency Syndromes
Antibody deficiencies and/or defects: 65%
Combined antibody and cellular deficiencies: 15%
Disorders of phagocytes: 10%
Isolated cellular defects (IE: T-cell problems): 5%
Disorders of the complement system: 5%
Other disorders of innate immunity: <1%

12. Match the deficiency with the clinical picture
Encapsulated bacterial infection
Disorders of antibodies (number or quality)
“Other” bacterial infection
Disorders of cell-mediated immunity
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Recurrent Neisseria infections
Disorders of complement

13. Match the deficiency with the clinical picture
Encapsulated bacterial infection
Disorders of antibodies (number or quality)
Recurrent and severe sinopulmonary infections with encapsulated bacterial strains (Streptococcus pneumoniae, Haemophilus influenzae)
Disorders of cell-mediated immunity
Disorders of phagocytosis
Disorders of complement

14. Match the deficiency with the clinical picture
Encapsulated bacterial infection
Disorders of antibodies (number or quality)
“Other” bacterial infection
Disorders of cell-mediated immunity
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Recurrent Neisseria infections
Disorders of complement

15. Match the deficiency with the clinical picture
Severe viral and/or bacterial illnesses or opportunistic infections*
Disorders of antibodies (number or quality)
“Other” bacterial infection
Disorders of cell-mediated immunity
Viral infection
Of course fungal and encapsulated are higher risk, but less a prominent feature. For instance, we don’t see a ton more aspergillosis in AIDS patients
Disorders of phagocytosis
Opportunistic infections
Disorders of complement

16. Match the deficiency with the clinical picture
Encapsulated bacterial infection
Disorders of antibodies (number or quality)
“Other” bacterial infection
Disorders of cell-mediated immunity
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Recurrent Neisseria infections
Disorders of complement

17. Match the deficiency with the clinical picture
Disorders of antibodies (number or quality)
“Other” bacterial infection
Disorders of cell-mediated immunity
Fungal infection
Disorders of phagocytosis
Recurrent and severe fungal (Candida and Aspergillus) and bacterial (Staphylococcus aureus, Pseudomonas aeruginosa, Nocardia asteroides, Salmonella typhi) infections in the skin and lung
Disorders of complement

18. Match the deficiency with the clinical picture
Encapsulated bacterial infection
Disorders of antibodies (number or quality)
“Other” bacterial infection
Disorders of cell-mediated immunity
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Recurrent Neisseria infections
Disorders of complement

19. Match the deficiency with the clinical picture
Disorders of antibodies (number or quality)
Disorders of cell-mediated immunity
Recurrent Neisserial infections at any age
Multiple family members who have experienced Neisserial infections
Disorders of phagocytosis
Recurrent Neisseria infections
Disorders of complement

20. Overview of Immunodeficiency Syndromes
Antibody deficiencies and/or defects: 65%
Combined antibody and cellular deficiencies: 15%
Disorders of phagocytes: 10%
Isolated cellular defects (IE: T-cell problems): 5%
Disorders of the complement system: 5%
Other disorders of innate immunity: <1%

21. Match the deficiency with the clinical picture
Encapsulated bacterial infection
Disorders of antibodies (number or quality)
Recurrent and severe sinopulmonary infections with encapsulated bacterial strains (Streptococcus pneumoniae, Haemophilus influenzae)
Disorders of cell-mediated immunity
Disorders of phagocytosis
Disorders of complement

22. Antibody deficiency/defect in adults
Common-variable immunodeficiency (CVID)
IgA deficiency
Asymptomatic, to recurrent sinopulmonary and GI bacterial infections
IgG subclass deficiency
Sinopulmonary bacterial infections
Non-specific immunoglobulin loss (bone marrow invasion; nephrotic syndrome; protein-losing enteropathy)
Antibodies defective (normal levels but efficacy is poor; lymphoma good example)
Measure immunoglobulin levels
Measure response to tetanus vaccine and/or pneumococcal vaccine

23. Common-Variable Immunodeficiency
Primary immunodeficiency disorder characterized by impaired B cell differentiation with defective immunoglobulin production
Markedly reduced IgG, in combination with low levels IgA and/or IgM
Poor or absent response to immunizations
80% of patients diagnosed from age 20-45
Encapsulated bacterial infection of sino-pulmonary tract is a prominent feature
Also at high risk for all bacterial infections (especially GI tract), giardia, mycobacteria, autoimmune disease, and malignancy

24. Overview of Immunodeficiency Syndromes
Antibody deficiencies and/or defects: 65%
Combined antibody and cellular deficiencies: 15%
Disorders of phagocytes: 10%
Isolated cellular defects (IE: T-cell problems): 5%
Disorders of the complement system: 5%
Other disorders of innate immunity: <1%

25. Combined antibody and cellular deficiencies
Less common in adults
Things like Severe Combined Immuno-Deficiency (SCID), Wiskott- Aldrich syndrome, Ataxia-telangiectasia, DiGeorge syndrome
There are a lot of these things but they are almost entirely pediatrics issues…

26. Overview of Immunodeficiency Syndromes
Antibody deficiencies and/or defects: 65%
Combined antibody and cellular deficiencies: 15%
Disorders of phagocytes: 10%
Isolated cellular defects (IE: T-cell problems): 5%
Disorders of the complement system: 5%
Other disorders of innate immunity: <1%

27. Match the deficiency with the clinical picture
Disorders of antibodies (number or quality)
“Other” bacterial infection
Disorders of cell-mediated immunity
Fungal infection
Disorders of phagocytosis
Recurrent and severe fungal (Candida and Aspergillus) and bacterial (Staphylococcus aureus, Pseudomonas aeruginosa, Nocardia asteroides, Salmonella typhi) infections in the skin and lung
Disorders of complement

28. Disorders of phagocytosis
Chronic Granulomatous Disease (CGD)
Recurrent, life-threatening bacterial and fungal infections with granuloma formation
Skin and lung most common sites of infection
Failure of “oxidative burst” means phagocytes cannot kill bacteria/fungi with H2O2 as usual
Nitroblue tetrazolium (NBT) reduction test directly measures oxidative burst
Management: early treatment of infections; prophylaxis with Bactrim, azole, and even interferon. Patients now living to middle-age.
Chediak-Higashi syndrome
Aberrant fusion of neutrophil vesicles
“Giant” inclusion bodies

29. Overview of Immunodeficiency Syndromes
Antibody deficiencies and/or defects: 65%
Combined antibody and cellular deficiencies: 15%
Disorders of phagocytes: 10%
Isolated cellular defects (IE: T-cell problems): 5%
Disorders of the complement system: 5%
Other disorders of innate immunity: <1%

30. Match the deficiency with the clinical picture
Severe viral and/or bacterial illnesses or opportunistic infections*
Disorders of antibodies (number or quality)
“Other” bacterial infection
Disorders of cell-mediated immunity
Viral infection
Of course fungal and encapsulated are higher risk, but less a prominent feature. For instance, we don’t see a ton more aspergillosis in AIDS patients
Disorders of phagocytosis
Opportunistic infections
Disorders of complement

31. Defects in cellular immunity
T-cell defects lead to B-cell defects, so often immunoglobulin problems as well
Can use a T-cell functional assay: “cutaneous delayed-type hypersensitivity” test
Analogous to PPD
Subcutaneous Candida antigen, measure in hours. Induration > 5mm is positive test
More advanced: take peripheral T-cells in a tube, add a known antigen and radiolabeled thymidine, see how much thymidine is taken up (marker for appropriate clonal expansion)
Flow cytometry accurately defines T-cell subpopulation deficiency and can be helpful

32. Flow Cytometry can be helpful for defining cell-mediate immunodeficiency

33. Overview of Immunodeficiency Syndromes
Antibody deficiencies and/or defects: 65%
Combined antibody and cellular deficiencies: 15%
Disorders of phagocytes: 10%
Isolated cellular defects (IE: T-cell problems): 5%
Disorders of the complement system: 5%
Other disorders of innate immunity: <1%
Terminal complement cascade deficiency increases Neisseria risk
Measure convalescent complement levels
Consider SLE

34. Back to the case
63yoM, history of thymoma with possible recurrence, HIV negative, now admitted with: Candida esophagitis, CMV colitis, PCP, Salmonella bacteremia, giardia
How to work him up?
Encapsulated bacterial infection
Disorders of antibodies (number or quality)
“Other” bacterial infection
Viral infection
Disorders of cell-mediated immunity
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Recurrent Neisseria infections

35. Immunoglobulin levels IgG subclass levels
Disorders of cell-mediated immunity
Disorders of antibodies (number or quality)
Immunoglobulin levels
IgG subclass levels
Response to tetanus and pneumococcal (PCV13 vaccine)
T-cell lymphocyte panel
T-cell functional assay
Encapsulated bacterial infection
Disorders of antibodies (number or quality)
“Other” bacterial infection
Viral infection
Disorders of cell-mediated immunity
Opportunistic infections

36. Course continued Severe immunoglobulin deficiency found (IgG level 76)
Poor IgG response to tetanus and PCV13 vaccination
T-cell sub-population panel shows CD4 count 231
T-cell functional assay shows minimal induration
Combined immunoglobulin and T-cell level/function deficiency diagnosed

37. Thymoma-associated paraneoplastic disorders

38. Good’s syndrome (thymoma with immunodeficiency) is a rare cause of combined B and T cell immunodeficiency in adults.
The clinical characteristics of Good’s syndrome are increased susceptibility to bacterial infections with encapsulated organisms and opportunistic viral and fungal infections

39. Patient outcome
He is started on ganciclovir, fluconazole, ceftriaxone, Bactrim, and metronidazole
Discharged home after 35 day admission on valgancyclovir, fluconazole, and Bactrim prophylaxis
His recurrent thymoma is treated
Several more infections, though overall doing well

40. Work-up to Immunodeficiency
Thorough infectious disease history. Figure out what categories they fall into
Eg: “recurrent sinopulmonary bacterial infection”, “recurrent skin infections”, “opportunistic infections”
Encapsulated bacterial infection
“Other” bacterial infection
Viral infection
Fungal infection
Opportunistic infections
Recurrent Neisseria infections

41. Work-up to Immunodeficiency
Match each category to expected immune system deficiency
If recurrent encapsulated sinopulmonary infection, think immunoglobulin deficiency; if recurrent viruses and OI’s, think T-cells
Encapsulated bacterial infection
Disorders of antibodies (number or quality)
“Other” bacterial infection
Disorders of cell-mediated immunity
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Recurrent Neisseria infections

42. Work-up to Immunodeficiency
Assay those parts of the immune system
Disorders of antibodies (number or quality)
Disorders of cell-mediated immunity
Immunoglobulin levels
IgG subset levels
Response to tetanus/PCV13 vaccination
T-lymphocyte panel
T-cell functional assay
Disorders of phagocytosis
Disorders of complement
Oxidative burst assay (NBT)
Blood smear
Convalescent complement levels

43. Work-up to Immunodeficiency
Once you’ve defined what components of the immune system are down, considering the patients age and clinical context, hit the books (or UpToDate) to see what specific syndrome is a match

44. Congratulations on finishing the Primary Immunodeficiency Module!
Please take this brief pre-module quiz