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