1. Extern Conference 12 July 2007

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

3. 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. History of present illness

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

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

6. She is 3 rd child of family. Her sister had history of recurrent otitis media about 5 times/yr, recurrent skin abscess that needed iv ATB and died from severe septicemia after ruptured appendicitis when she was 14 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. Family history

7. Pedigree 14 years 10 months 8 years 43 years39 years

8. Physical examination at LOEI V/S : T 39.4 ۫C BP 110/60 mmHg HR 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. 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 Investigation

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-treatment Skin 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. Purple-black colonies on blood agar plate Chromobacterium violaceum

15. The patient was referred to Siriraj Hospital Why?

16. Problem List 1.Severe skin infection with pneumonia and sepsis from an unusual pathogen 2.Family history of recurrent severe skin infection 3.Consanguinity of parents 4.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. 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 10 Warning signs 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. 1. Innate immunity –Non-specific, no memory –eg. Phagocyte (neurophils, monocyte, eosinophils), complement, skin, mucosal membrane Immune system

22. Innate immunity Phagocyte –recognize, engulf and destroy pathogen esp. bacteria and fungus –Killing mechanism via lysosomal enzymes (O 2 indenpendent) or free radical (O 2 dependent)

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

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

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

26. 2.Cellular (cell-mediated) immune response –Mediated by antigen- specific cells called T lymphocyte via the antigen presenting cells –Specific to intracellular pathogen eg. virus, higher bacteria and fungus Adaptive immunity

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 – The B-lymphocyte system – The T-lymphocyte system – The Phagocytic system – The Complement system

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

30. CharacteristicT cell defectB cell defectPhagocyte defectComplement defect Age of onsetEarly onset, 2-6 months After maternal Ab diminish Early onsetAny age Specific pathogens Bacteria: Mycobacteria Virus: EBV, varicella, enterovirus Fungus&parasite: candida, PCP Bacteria: Streptococcus Staphylococcus Haemophilus Campylobactor Virus: Enterovirus Fungus&parasite: giardia cryptosporidia Bacteria: Staphylococcus Pseudomonas Serratia Klebsiella Fungus&parasite: Candida, norcadia, aspergillus Bacteria: Neisseria E.coli Thomas A. Fleisher and Mark Ballow, Pediatric clinics of north america: December 2000

31. CharacteristicT cell defectB cell defectPhagocyte defectComplement defect Affected organs FTT, Protracted diarrhea, Extensive mucocutaneous scandidiasis Recurrent sinopulmonary infections, Chronic GI symproms, Malabsorption, Arthritis, Enteroviral meningoencephalitis Skin: dermatitis, impetigo, cellulitis LN: suppurative adenitis Oral cavity: Periodontotis Ulcer Internal organ abscess osteomyelitis Infection: Meningitis Arthritis Septicemia Recurrent sinopulmonary infections Thomas A. Fleisher and Mark Ballow, Pediatric clinics of north america: December 2000

32. CharacteristicT cell defectB cell defectPhagocyte defect Complement defect Special features GVHD Disseminated BCG or paralytic polio Hypocalcemic tetany of infancy Autoimmunity Lymphoreticular malignancy Lymphoma Thymoma Postvaccination paralytic polio Prolonged attachment of umbilical cord Poor wound healing Rheumatoid arthritis SLE Vasculitis Dermatomyositis Scleroderma Glomerulonephritis angioedema 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. 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 Approach to this patient

35. Chronic granulomatous disease ( CGD )

36. 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 Diagnosis of CGD

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 1 o Immune Deficency”

43. Thank you for your attention