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Clinical Cases: Diagnosis and Management of Primary
Immunodeficiency Around the World
Elham Hossny, MD, PhD, FAAAAI Ain Shams University, Egypt
Primary Immune Deficiency: A Global Perspective Friday, February 28, 2014: 2:00 PM-5:00 PM
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
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;167:108-19.
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.
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
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.
PAD 38%
CID 22%
Other well
defined 16%
Phagocyte 20%
Others
4%
Distribution of a group of Egyptian PID patients
Total number of patients = 291
Pediatric Allergy and Immunology (PAI) Unit Children’s Hospital, Ain Shams University, Egypt
Fig 1
Journal of Allergy and Clinical Immunology 2013; 131:658-660.
Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions
Al-Herz W, Al-Mousa H. Combined immunodeficiency: the Middle East experience
Characteristics of Primary Immunodeficiency According to the Immune Defect
PID Disorder Age of Onset
Predominant T-cell
defect Early, usually 2–6 mo of
age
Predominant B-cell
defect After maternal antibodies
diminish (after 5–7 mo),
or later childhood
Granulocyte defect Early onset
Complement defect Any age
Adapted from Woroniecka M, Ballow M. Pediatr Clin North Am 2000;47:1211–24.
Characteristics of PIDD (cont’d)
PID Disorder Affected Organs
Predominant T-cell defect
• Failure to thrive, protracted diarrhea • Extensive candidiasis
Predominant B-cell defect
• Recurrent sinopulmonary infections • Chronic diarrhea & malabsorption • Arthritis • Enteroviral meningoencephalitis
Granulocyte defect • Skin and organ abscesses • Periodontitis • Osteomyelitis
Complement defect • Meningitis • Arthritis • Septicemia
Adapted from Woroniecka M, Ballow M. Pediatr Clin North Am 2000;47:1211–24.
Characteristics of PIDD (cont’d)
PID Disorder Other Features
Predominant T-cell
defect
• GVHD due to maternal engraftment or non-irradiated blood transfusion
• Postvaccination disseminated BCG or varicella
• hypocalcemic tetany in infancy
Predominant B-cell
defect
• 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;47:1211–24.
Features Associated with Primary Immunodeficiency
Dermatologic Disorder
Eczema Wiskott-Aldrich syndrome
Eczema + recurrent skin abscesses Hyper-IgE syndrome
Hypopigmented hair; albinism Chediak-Higashi syndrome
Oculocutaneous telangiectasia Ataxia-telangiectasia
Oral or nail candidiasis T-cell immune defects; combined defects; mucocutaneous candidiasis
Vitiligo B-cell defects
Alopecia B-cell defects
Severe dermatitis Omenn syndrome
Adapted from Goldman L, Ausiello D. Cecil Textbook of Medicine. 22nd edition. Philadelphia: WB Saunders; 2004. p.1599.
Features Associated with PIDD (cont’d)
Extremities Disorder
Clubbing of the nails Chronic lung disease due to antibody defects
Arthritis Antibody defects, Wiskott-Aldrich syndrome, hyper-IgM
Bony dysplasia ADA deficiency, SCID
Hyper-laxity of joints 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; 2004. p.1599.
Features Associated with PIDD (cont’d)
Endocrine Disorder
Growth hormone
deficiency
X-Linked
agammaglobulinemia
Gonadal dysgenesis Mucocutaneous
candidiasis
Hypoparathyroidism DiGeorge syndrome
Adapted from Goldman L, Ausiello D. Cecil Textbook of Medicine. 22nd edition. Philadelphia: WB Saunders; 2004. p.1599.
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/mm3
• Absolute neutrophil count:
normal result rules against congenital or acquired neutropenia
elevated counts are present in LAD even between infections
Investigations Used in Screening for PIDD
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)
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
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
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.
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.
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:CR217-25.
Flow chart for evaluation of humoral immunity
Immuno-globulin
quantitation
Anti-A, Anti-B iso-
hemagglutinins
Enumeration of B
lymphocytes (flow-
cytometry)
Response to Vaccination
Functional Studies
Adapted from Folds JD, Schmitz JL. J Allergy Clin Immunol 2003;111:S702-11
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
Classification of SCID according to lymphocyte phenotyping (examples)
T-
B-NK-
B+ NK-
B- NK+
B+ NK+
ADA deficiency IL-7Rα
deficiency
X-linked SCID Jak-3 deficiency CD 45 deficiency
RAG-1 RAG-2
Artemis deficiency
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
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
ACKNOWLEDGEMENTS
Yehia El-Gamal Khaled Awwad Zeinab Awad Shereen Reda Zeinab Hasan
Shereen El-Sayed
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
PAI Team, Children’s Hospital, Ain Shams university
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