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Extern Conference 12 July 2007 8-year-old Thai girl, from LOEI Chief Complaint : Fever with pustules at her both legs for 2 days 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. 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 Past history • 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 2nd grade Family history • She is 3rd 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. Pedigree 43 years 39 years 14 years 10 months 8 years 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 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 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 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 Post-treatment Skin lesions 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 Chromobacterium violaceum Purple-black colonies on blood agar plate The patient was referred to Siriraj Hospital Why? 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 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 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 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 Immune system Immune system 1. Innate immunity – Non-specific, no memory – eg. Phagocyte (neurophils, monocyte, eosinophils), complement, skin, mucosal membrane Innate immunity • Phagocyte – recognize, engulf and destroy pathogen esp. bacteria and fungus – Killing mechanism via lysosomal enzymes (O2indenpendent) or free radical (O2 dependent) Innate immunity • Complement : Group of proteins containing of plasma proteins and membrane protein 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 Adaptive immunity 1. Humoral (Antibodymediated) immune response – Antibodies are produced by plasma cells (antigen-specific B lymphocyte) Adaptive immunity 2.Cellular (cell-mediated) immune response – Mediated by antigenspecific cells called T lymphocyte via the antigen presenting cells – Specific to intracellular pathogen eg. virus, higher bacteria and fungus 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 Primary Immunodeficiency Diseases • Divided in 4 functional compartments – – – – The B-lymphocyte system The T-lymphocyte system The Phagocytic system The Complement system Epidermiology Complement 2% Phagocyte 18% Cellular&Antibody 20% Cellular 10% Antibody 50% Stiehm, 4th ed, 1996 Characteristic T cell defect B cell defect Phagocyte defect Complement defect Age of onset Early onset, 2-6 months After maternal Ab diminish Early onset Any age Specific pathogens Bacteria: Mycobacteria Virus: EBV, varicella, enterovirus Fungus¶site: candida, PCP Bacteria: Streptococcus Staphylococcus Haemophilus Campylobactor Virus: Enterovirus Fungus¶site: giardia cryptosporidia Bacteria: Staphylococcus Pseudomonas Serratia Klebsiella Fungus¶site: Candida, norcadia, aspergillus Bacteria: Neisseria E.coli Thomas A. Fleisher and Mark Ballow, Pediatric clinics of north america: December 2000 Characteristic Affected organs T cell defect FTT, Protracted diarrhea, Extensive mucocutaneous scandidiasis B cell defect Phagocyte defect Complement defect 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 Characteristic Special features T cell defect GVHD Disseminated BCG or paralytic polio Hypocalcemic tetany of infancy B cell defect Phagocyte defect Autoimmunity Lymphoreticular malignancy Lymphoma Thymoma Postvaccination paralytic polio Prolonged attachment of umbilical cord Poor wound healing Complement defect Rheumatoid arthritis SLE Vasculitis Dermatomyositis Scleroderma Glomerulonephritis angioedema Thomas A. Fleisher and Mark Ballow, Pediatric clinics of north america: December 2000 Approach to this patient • Differential diagnosis 1. Phagocytic disorders 2. B-cell disorders 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 Chronic granulomatous disease ( CGD ) 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 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 Diagnosis Primary immunodeficiency : Phagocytic disorder (Chronic granulomatous disease) Management • • • • • Treat infection Antibiotic prophylaxis Avoid infection Counseling Specific treatment – Bone marrow transplant – Gene therapy 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 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” Thank you for your attention