Clinical Cases: Diagnosis and Management of Primary Immunodeficiency Around the World

Transcription

1 Primary Immune Deficiency: A Global Perspective Friday, February 28, 2014: 2:00 PM-5:00 PM Clinical Cases: Diagnosis and Management of Primary Immunodeficiency Around the World Elham Hossny, MD, PhD, FAAAAI Ain Shams University, Egypt

2 Primary immunodeficiency disorders (PIDD) are under-diagnosed in many parts of the world due to: 1. Lack of screening during the perinatal period or early childhood. 2. Extensive use of antibiotics masks the classic presentation of many PIDD. Buckley RH. Nelson Textbook of Pediatrics, 2011

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4 Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update de Vries E; European Society for Immunodeficiencies (ESID) members. Clin Exp Immunol 2012;167: The multi-stage design allows cost-effective screening for PID of the large number of potential cases in the early phases, with more expensive tests reserved for definitive classification at a later stage.

5 Family history in the screening for PIDD History of known PIDD in the family* History of sib death due to recurrent or severe infection* History of unexplained death of more than one sib* *The presence of parental consanguinity is supportive

6 Family history in the screening for PIDD (cont d) Family history of death or recurrent infections in a maternal uncle: X-linked disorders (e.g. X-linked SCID; X-linked agammaglobulinemia; Wiskott-Aldrich syndrome; CGD). Familial clustering of autoimmune disorders (e.g., SLE; pernicious anemia): common variable immunodeficiency or selective IgA deficiency.

7 Distribution of a group of Egyptian PID patients Others 4% Total number of patients = 291 Phagocyte 20% PAD 38% Other well defined 16% CID 22% Pediatric Allergy and Immunology (PAI) Unit Children s Hospital, Ain Shams University, Egypt

8 Fig 1 Al-Herz W, Al-Mousa H. Combined immunodeficiency: the Middle East experience Journal of Allergy and Clinical Immunology 2013; 131: Copyright 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Characteristics of Primary Immunodeficiency According to the Immune Defect PID Disorder Predominant T-cell defect Predominant B-cell defect Granulocyte defect Complement defect Age of Onset Early, usually 2 6 mo of age After maternal antibodies diminish (after 5 7 mo), or later childhood Early onset Any age Adapted from Woroniecka M, Ballow M. Pediatr Clin North Am 2000;47:

10 Characteristics of PIDD (cont d) PID Disorder Predominant T-cell defect Predominant B-cell defect Granulocyte defect Complement defect Affected Organs Failure to thrive, protracted diarrhea Extensive candidiasis Recurrent sinopulmonary infections Chronic diarrhea & malabsorption Arthritis Enteroviral meningoencephalitis Skin and organ abscesses Periodontitis Osteomyelitis Meningitis Arthritis Septicemia Adapted from Woroniecka M, Ballow M. Pediatr Clin North Am 2000;47:

11 Characteristics of PIDD (cont d) PID Disorder Other Features Predominant T-cell defect Predominant B-cell defect GVHD due to maternal engraftment or nonirradiated blood transfusion Postvaccination disseminated BCG or varicella hypocalcemic tetany in infancy Autoimmunity Lymphoreticular malignancy Postvaccination paralytic polio Granulocyte defect Prolonged attachment of umbilical cord Poor wound healing Complement defect Rheumatologic disorders: SLE Glomerulonephritis Angioedema Adapted from Woroniecka M, Ballow M. Pediatr Clin North Am 2000;47:

12 Features Associated with Primary Immunodeficiency Dermatologic Eczema Eczema + recurrent skin abscesses Hypopigmented hair; albinism Oculocutaneous telangiectasia Oral or nail candidiasis Vitiligo Alopecia Severe dermatitis Disorder Wiskott-Aldrich syndrome Hyper-IgE syndrome Chediak-Higashi syndrome Ataxia-telangiectasia T-cell immune defects; combined defects; mucocutaneous candidiasis B-cell defects B-cell defects Omenn syndrome Adapted from Goldman L, Ausiello D. Cecil Textbook of Medicine. 22nd edition. Philadelphia: WB Saunders; p.1599.

13 Features Associated with PIDD (cont d) Extremities Clubbing of the nails Arthritis Bony dysplasia Hyper-laxity of joints Disorder Chronic lung disease due to antibody defects Antibody defects, Wiskott- Aldrich syndrome, hyper- IgM ADA deficiency, SCID Hyper-IgE syndrome Short-limb dwarfism Short-limb dwarfism with T- and/or B-cell defects Adapted from Goldman L, Ausiello D. Cecil Textbook of Medicine. 22nd edition. Philadelphia: WB Saunders; p.1599.

14 Features Associated with PIDD (cont d) Endocrine Growth hormone deficiency Gonadal dysgenesis Hypoparathyroidism Disorder X-Linked agammaglobulinemia Mucocutaneous candidiasis DiGeorge syndrome Adapted from Goldman L, Ausiello D. Cecil Textbook of Medicine. 22nd edition. Philadelphia: WB Saunders; p.1599.

15 Investigations Used in Screening for PIDD CBC, manual differential, and ESR: Absolute lymphocyte count (normal result rules against T-cell defect): At nine mo, lower limit of normal is 4,500/mm 3 Absolute neutrophil count: normal result rules against congenital or acquired neutropenia elevated counts are present in LAD even between infections

16 CBC, manual differential, and ESR (cont d) Platelet count (normal result excludes Wiskott-Aldrich syndrome) Howell-Jolly bodies (absence rules against asplenia) ESR (normal result indicates that chronic bacterial or fungal infection unlikely)

17 Investigations used in screening for PIDD (cont d) Screening tests for B-cell defects: IgA measurement; if abnormal, IgG and IgM measurement Isohemagglutinins A and B Antibody titers to tetanus, diphtheria, Haemophilus influenzae, and S. pneumoniae

18 Investigations used in screening for PIDD (cont d) Screening tests for T-cell defects: Absolute lymphocyte count (normal result indicates that T-cell defect is unlikely) Candida albicans intradermal skin test: 0.1 ml of a 1:1,000 dilution for patients 6 yr, 0.1 ml of a 1:100 dilution for patients <6 yr

19 Investigations used in screening for PIDD (cont d) Screening tests for phagocytic cell defects: Absolute neutrophil count Respiratory burst assay by flowcytometry: This is the most reliable and useful test (flow cytometry assessment of the respiratory burst using rhodamine dye) This test has replaced the previously used nitroblue tetrazolium (NBT) dye test.

20 Investigations used in screening for PIDD (cont d) Screening test for complement deficiency: CH50 It measures the amount of complement in serum required to lyse 50% of red blood cell targets. This test measures both the classic and alternative complement pathways because it relies on properly formed C9 complement pores, which are the end products of both pathways.

21 Results of laboratory screening of 100 Children suspected to have PID according to the 10 warning signs Hossny E, et al. Med Sci Monit 2009;15:CR

22 Flow chart for evaluation of humoral immunity Immunoglobulin quantitation Anti-A, Anti-B isohemagglutinins Enumeration of B lymphocytes (flowcytometry) Response to Vaccination Functional Studies Adapted from Folds JD, Schmitz JL. J Allergy Clin Immunol 2003;111:S702-11

23 Flow chart for evaluation of cellular immunity CBC with differential Lymphocyte subsets Candida intradermal testing In vitro LPA Adapted from Folds JD, Schmitz JL. J Allergy Clin Immunol 2003;111:S702-11

24 Classification of SCID according to lymphocyte phenotyping (examples) IL-7Rα deficiency B- NK- ADA deficiency B+ NK+ T- B+ NK- RAG-1 RAG-2 Artemis deficiency B- NK+ X-linked SCID Jak-3 deficiency CD 45 deficiency

25 Flow chart for evaluation of complement deficiency CH50 Measurement of complement components Functional assessment of complement components Adapted from Folds JD, Schmitz JL. J Allergy Clin Immunol 2003;111:S702-11

26 Global challenges to effective treatment of PIDD Delayed diagnosis and referral The early administration of BCG without screening for PIDD Physicians and patients have encountered a number of challenges to administering and receiving appropriate immunoglobulin therapy. The variable availability of HSCT worldwide

27 Yehia El-Gamal Khaled Awwad Zeinab Awad Shereen Reda Zeinab Hasan Shereen El-Sayed ACKNOWLEDGEMENTS PAI Team, Children s Hospital, Ain Shams university Dalia El-Ghoneimy Reem Elfeky Rasha El-Oweidy Hanan Lateef Nesreen Radwan Neveen Ali International Lab Support Luigi Notarangelo Raif Geha Michel Massaad Francesco Frugoni Jennifer Kane Ain Shams PAI Lab Eman Ghanem Eman Ibraheim