1. Immune Deficiency Syndromes in the Appalachia Presented by: Demetrio R. Macariola, M.D. FAAP THINK BEYOND THE BUGS

2. Disclosure Statement of Financial Interest I, Demetrio R. Macariola, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation

3. Disclosure Statement of Unapproved/Investigative Use I, Demetrio Macariola, DO/DO NOT anticipate discussing the unapproved/investigative use of a commercial product/device during this activity or presentation.

4. 1. Describe the different immune deficiency syndromes in our community in outpatient setting. 2. Describe the pathogens associated with each deficiency syndrome. Learning Objectives

5. Immune Deficiency Syndromes in the Appalachia over 4 years CVID: 20 Agammaglobulinemia: 2 Transient Hypogammaglobulinemia: 2 Chronic Granulomatous Disease: 4 Hyper IgE Syndrome: 2 HIV: 1 TOTAL: 35

6. “MY CHILD IS ALWAYS SICK” 4 year old boy who developed pneumococcal pneumonia and bacteremia at 8 months later on developing E. coli UTI at 10 months and non typeable H. influenzae bacteremia at 2 years of age. Had been having recurrent pneumonia and sinusitis that mom thinks he cannot get over it.”. PE unremarkable.

7. Laboratories Initial immunoglobulin levels: IgM: low, IgG: normal, IgE: normal After 2 weeks: immunoglobulin levels: IgM normal, IgG: low, IgE: normal Diptheria and Tetanus titers: non protective CD 19 lymphocyte count: normal

8. Differential Diagnosis? 1. Common Variable Immunoglobulin Deficiency 2. Transient Hypogammaglobulinemia 3. Agammaglobulinemia 4. Hyper IgE Syndrome

9. Common Variable Immunoglobulin Deficiency Infections usually occurs after 6 months Can affect both genders Non protective diphteria and tetanus titers Treatment: Immunoglobulins

10. “Something not right is going on” 2 month old boy previously healthy developed right leg weakness after getting oral polio vaccine. His dad is concern that “ something not right is going on”. PE: right lower extremity weakness.

11. Laboratories Initial : IgM, IgG, IgA non detectable Repeat: immunoglobulin levels non detectable CD 19 lymphocyte count : zero

12. Differential Diagnosis 1. Agammaglobulinemia 2. Transient hypogammaglobulinemia 3. Hyper IgE syndrome 4. Chronic granulomatous disease

13. Agammaglobulinemia May be autosomal recessive or X-linked All immunoglobulins and CD 19 lymphocytes are non detectable.

14. “We belong to a family with immunoglobulin deficiencies” 9 month old girl who had 2 episodes of otitis media within 3 months. No other infections. PE in unremarkable. Two family members with CVID.

15. Laboratories IgA normal, low IgM IgG Diphteria and tetanus titers: normal CD 19 lymphocytes: normal

16. Differential Diagnosis 1. Agammaglobulinemia 2. Transient hypogammaglobulinemia 3. Hyper IgE syndrome 4. Chronic granulomatous disease

17. Transient Hypogammaglobulinemia of Infancy (THI) Low immunoglobulin levels that resolves between 2-3 years old. Normal diphteria and tetanus titers Normal CD 19 lymphocyte counts

18. “Rashes, asthma & infections not going away” 15-year-male presented with recurrent pneumonia and sinusitis. Pneumatocele was observed in the chest Xray. Had several episodes of sinusitis and pneumonia in the past. Had been having moderate to severe asthma. PE findings pertinent for eczema and crackles.

19. Laboratories IgG, IgM levels: normal IgE level: 3000 mg/dl Blood culture: S. aureus

20. Differential Diagnosis 1. Agammaglobulinemia 2. Transient hypogammaglobulinemia 3. Hyper IgE syndrome 4. Chronic granulomatous disease

21. Hyper IgE Syndrome Also known as Job syndrome Eczema, asthma, recurrent sinusitis, lymphadenitis Markedly elevated IgE level Elevated eosinophils

22. “Unusual germ from a facial wound” 3 year girl who developed cervical adenitis that did not improved with amoxicillin-clavulanate. The cervical adenitis recurred and was treated with trimethoprim- sulfamethoxazole with improvement.

23. Laboratories: Wound culture: Burkholderia cepacia Immunoglobulin levels: normal Neutrophil oxidative burst test: positive

24. Differential Diagnosis 1. Agammaglobulinemia 2. Transient hypogammaglobulinemia 3. Hyper IgE syndrome 4. Chronic granulomatous disease

25. Chronic Granulomatous Disease Can be autosomal recessive or x-linked Rx: Trimethoprim-sulfamethoxazole, itraconazole Gamma interferon

26. “My niece always have these skin bumps” 11 year old girl who lives with her aunt had been having repeated skin infections for 2 years. Had been on multiple antibiotics. Pertinent PE findings generalized impetigo and oral thrush.

27. Laboratories: Immunoglobulin levels: Elevated IgM, IgE, IgA and IgG CD4 count: low CBC: lymphopenia

28. Differential Diagnosis 1. CVID 2. Hyper IgE syndrome 3. Hyper IgM syndrome 4. HIV

29. IMMUNOGLOBULIN DEFICIENCY SYNDROMES IN OUR AREA 1. Hypogammaglobulinemia- X-linked, autosomal recessive 2. Common Variable Immunoglobulin Deficiency 3. Transient Hypogammaglobulinemia of Infancy 4. Hyper IgE Syndrome/Job syndrome

30. Pathogens Commonly Affecting Patients with CVID and Agammaglobulinemia 1.Encapsulated bacteria: Pneumococcus, E.coli, H. influenzae, Salmonella, Mycoplasma 2. Viruses: enteroviruses, hepatitis C, CMV, VZV 3. Parasite: Giardia

31. Pathogens Commonly Affecting Patients with CGD Bacteria: S. aureus, Serratia marcescens, B. cepacia, Nocardia. Fungi: Aspergillus

32. Pathogens Commonly Affecting Patients with Hyper IgE S. aureus

33. Chest xray Lobar PneumoniaPneumatocele

34. Pathogens & Associated Conditions E. coli sepsis: Galactosemia Recurrent Neisseria infection: Terminal Complement Deficiency Deep Candida Infection: Myeloperoxidase Deficiency Disseminated Maycobacterial Infection: T lymphocyte Deficiency P. jerovecii infection: T lymphocyte deficiency Encapsulated bacterial infection: Splenic Dysfuntion

35. 10 warning signs of Immune Deficiency  Eight or more new ear infections within one year.  Two or more serious sinus infections within 1 year.  Two or more months on antibiotics with little effect.  Two or more pneumonias within 1 year.  Failure of an infant to gain weight or grow normally.

36. 10 warning signs of Immune Deficiency  Recurrent, deep skin or organ abscesses.  Persistent thrush in mouth or elsewhere on skin, after 1 year.  Need for intravenous antibiotics to clear infections.  Two or more deep-seated infections such as sepsis, meningitis or cellulitis.  A family history of primary immune deficiency.

37. Review Question A 4-year-old boy was diagnosed to have chronic granulomatous disease which of the following may be used as prophylactic antibiotic treatment? A. ampicillin B. cephalexin C. trimethoprim-sulfamethoxazole D. ceftriaxone E. ertapenem

38. Review Question On a 6-year-old boy with recurrent meningococcal infection which of the following immune deficiency syndrome will you suspect? A. common variable immunoglobulin deficiency B. complement deficiency C. galactosemia D. Job syndrome E. Bruton’s agammaglobulinemia

39. References: 1. 2012 4 th edition Principles and Practice of Pediatric Infectious Diseases- Long, Pickering & Probe 2. 2012 edition AAP Red Book- Pickering 3. 2009 edition Principles and Practice of Infectious Diseases 4. Immune Deficiency Foundation Website- http://primaryimmune.org/ http://primaryimmune.org/

40. Special Thanks 1. To Ms. Danielle Crumly- ID clinic nurse 2. Colleagues 3. Residents and medical students who had rotated with pediatric ID. 4. Nurses at Niswonger Children Hospital 5. Nurses at ETSU Infusion Center