Extern Conference

1. Extern Conference 12 July 2007

2. 8-year-old Thai girl, from LOEI Chief Complaint : Fever with pustules at her both legs for 2 days

3. History of present illness 1 mo. PTA, She had high grade fever for 2 days after swimming with her father in a pond and developed few pustules at both legs. She was admitted at Na-Duang hospital and received Ceftriaxone for 1 day, but clinical seem to be worse. Then, she was referred to Loei hospital.

4. Past history • She had history of otitis media for 1 time and had recurrent oral ulceronce a week responsed to Kenalog for 1 year • No history of sinusitis, pneumonia, meningitis, chronic diarrhea or skin abscess before this time

5. Past history • Birth history:Term, NL, BW 3,400 gm,no perinatal complication, no delay detachment of umbilical cord • No history ofsurgery and significant illness • Immunization : Complete EPI program, no postvaccination complication • Allergies : no drugs or foods allergy • Development :Appropriate growth. Doing well in 2nd grade

6. Family history • She is 3rd child of family. • Her sister hadhistory of recurrent otitis media about 5 times/yr, recurrent skin abscess that needed iv ATBand died from severe septicemia after ruptured appendicitis when she was14 yr-old. • Her brother had history of recurrent skin abscess in the same way and died from severe septicemia at 10 months of age • There is a consanguinity marriage in her parents.

7. 43 years 39 years 14 years 10 months 8 years Pedigree

8. Physical examination at LOEI • V/S : T 39.4۫C BP 110/60mmHgHR 160/min RR 16/min • Wt 18.8 kg (P3-P10) Ht 119 cm (P10-P25) • GA: looked sick, mildly pale, no jaundice, dyspnea, a skin lesions were pustules and blebs looked like Ecthyma gangrenosum • RS : fine crepitation both lungs • Abdomen : soft, mild tender, liver just palpable, no splenomegaly

9. Investigation CBC (5/6/50) : Hb 10.7 g/dl, Hct 32%, MCV 63.6, MCH 19.5, Anisocytosis 1+, Hypochromic 1+, Microcytic 1+ WBC 18,600 (N68, Band19,L12) Platelet 188,000/ul UA (5/6/50) : WBC 1-2 RBC 0-1 Anti-HIV : Negative

10. Investigation Chest x-ray (7/6/50) : Consolidation at LLL could be due to bronchopneumonia with mild diffuse reticulonodular infiltration at both perihilar and both basal lung

11. Clinical course at LOEI • Rx : Cloxacillin and cefotaxime iv 2 days later, pustules were spread to all extremities. • Ix : H/C and Pus C/S was identified as “Chromobacterium violaceum”. Antibiotic was switched to Meropenem for 21 days. She responsed to treatment. • Dx: Skin infection with pneumonia with severe gram negative septicemia

12. Post-treatmentSkin lesions

13. Chromobacterium violaceum • Aerobic, gram-negative bacillus, catalase positive • Epidemiology : Worldwide, rare infection • Traumatic wound infection • Sepsis (mostly in neutropenic patients and in patients with chronic granulomatous disease) • Pneumonia after drowning

14. Chromobacterium violaceum Purple-black colonies on blood agar plate

15. The patient was referred to Siriraj Hospital Why?

16. Problem List • Severe skin infection with pneumonia and sepsis from an unusual pathogen • Family history of recurrent severe skin infection • Consanguinity of parents • Recurrent oral ulcer

17. 10 Warning signs of Primary Immune Deficiency • 8 or more new ear infections in 1 yr • 2 or more serious sinus infections in 1 yr • 2 or more months on ATB with little effect • 2 or more pneumonias in 1 yr • Failure to gain weight or grow normally

18. 10 Warning signs of Primary Immune Deficiency • Recurrent, deep skin or organ abscesses • Persistent thrush in mouth/skin after 1 yr • Need for iv antibiotic to clear infections • 2 or more deep-seated infection eg. meningitis, osteomyelitis, cellulitis or sepsis • Family history of primary immune deficiency

19. Immune Deficiency • Primary immune deficiency • Genetic inheritant : X-linked, Autosomal recessive, Autosomal dominant, Sporadic • Secondary immune deficiency • Acquired eg. HIV, hematologic malignancy, chemotherapy, immunosuppressive drugs, steroid use, Autoimmune diseases

20. Immune system

21. Immune system • Innate immunity • Non-specific, no memory • eg. Phagocyte (neurophils, monocyte, eosinophils), complement, skin, mucosal membrane

22. Innate immunity • Phagocyte • recognize, engulf and destroy pathogen esp. bacteria and fungus • Killing mechanism via lysosomal enzymes (O2indenpendent) or free radical (O2 dependent)

23. Innate immunity • Complement : Group of proteins containing of plasma proteins and membrane protein

24. Immune system 2. Adaptive immunity • Specific, memory by Ag exposure eg. Humoral immune system (B cell) from BM Cellular immune system (T cell) from thymus

25. Adaptive immunity 1. Humoral (Antibody-mediated) immune response • Antibodies are produced by plasma cells (antigen-specific B lymphocyte)

26. Adaptive immunity 2.Cellular (cell-mediated) immune response • Mediated by antigen-specific cells called T lymphocytevia the antigen presenting cells • Specific to intracellular pathogen eg. virus, higher bacteriaand fungus

27. What is primary immunodeficiency ? • Immune system is missing or doesn’t work correctly • 1/10,000 to 1/100,000 • Mostly inherited  • very mild to serious form

28. Primary Immunodeficiency Diseases • Divided in 4 functional compartments • TheB-lymphocyte system • The T-lymphocyte system • The Phagocytic system • The Complement system

29. Complement 2 % Phagocyte Cellular&Antibody 18 % 20 % Cellular 10 % Antibody 50 % Epidermiology Stiehm, 4th ed, 1996

30. Thomas A. Fleisher and Mark Ballow, Pediatric clinics of north america: December 2000

31. Thomas A. Fleisher and Mark Ballow, Pediatric clinics of north america: December 2000

32. Thomas A. Fleisher and Mark Ballow, Pediatric clinics of north america: December 2000

33. Approach to this patient • Differential diagnosis 1. Phagocytic disorders 2. B-cell disorders

34. Approach to this patient Phagocytic disorders • Skin abscess • Family history of recurrent severe skin infection • Family history with consanguinity of parents : CGD Autosomal recessive type • H/C and pus C/S : Chromobacterium violaceum (atypical pathogen) common in CGD

35. Chronic granulomatous disease( CGD )

36. Diagnosis of CGD • The NBT test is based on microscopic evaluation of a limited number of cells. the NBT test may accumulate positive staining over time. • DHR : a fluorescent assay using the conversion of dihydroxyrhodamine 123 (DHR) to rhodamine 123 not only diagnose CGD but also suggest the CGD genotype

37. Investigation Immunoglobulin level(5/7/50) • IgG : 2,700 mg/dl (411-1435) • IgA : 677 mg/dl (34-214) • IgM : 203 mg/dl (15-115) • IgE : <4.41 IU/ml (<90) DHR (5/7/50) : Abnormal

38. Diagnosis Primary immunodeficiency : Phagocytic disorder (Chronic granulomatous disease)

39. Management • Treat infection • Antibiotic prophylaxis • Avoid infection • Counseling • Specific treatment • Bone marrow transplant • Gene therapy

40. Management in this patient • Antibiotic prophylaxis • Cotrimoxazole (80/400) 1 tab oral pc morning, ½ tab oral pc evening • Itraconazole (100) 1 tab oral OD morning • Refer to Loei hospital for U/S abdomen

41. Take Home Message Awareness about the patient that have 1. Recurrent infection 2. Uncommon organism 3. Increased dependency on ATB 4. Family history of severe infection “10 Warning sign of 1o Immune Deficency”

43. Thank you for your attention