When should a Primary Immunodeficiency be Suspected?

When should a Primary Immunodeficiency be Suspected? Ricardo U Sorensen. MD Head, Jeffrey Modell Diagnostic Center for Primary Immunodeficiencies. LSUHSC, New Orleans

Learning Objectives Define Primary Immunodeficiency Diseases (PIDD) Warning signs of a PIDD Evaluation for PIDD Referral recommendations

Learning Objectives Define Primary Immunodeficiency Diseases (PIDD) Warning signs of a PIDD Evaluation for PIDD Referral recomendations

Primary Immunodeficiency diseases (PIDD) PIDD are monogenic or polygenic disorders that are present during the patients lifetime and affect one or several components of the immune system. PIDs can present clinically at any age Some improve due to compensatory mechanisms, others develop or get worse with age.

Components of Immunity and PID Cell Mediated Immunity Antibody Mediated Immunity Phagocytosis Complement Innate Immunity Regulation of inflammation and fever Regulation of cell proliferation and self recognition

Components of Immunity and PIDD Cell Mediated Immunity Antibody Mediated Immunity Phagocytosis Complement Innate Immunity Regulation of inflammation and fever Regulation of cell proliferation and self recognition Combined T and B cell ID Combined with syndrome features Predominantly Antibody ID Congenital defects of phagocytes Complement deficiencies Defects in innate immunity Autoinflammatory disorders Diseases of immune dysregulation

Increase in Recognition of New Primary Immunodeficiencies 2006 2009 2014 Combined T and B cell ID 21 26 41 Combined ID with other syndromes 12 16 37 Predominantly Antibody ID 12 23 35 Congenital defects of phagocytes 20 26 37 Complement deficiencies 18 24 28 Defects in innate immunity 7 10 24 Diseases of immune dysregulation 9 18 35 Autoinflammatory disorders 8 9 20 2015 ~270 molecularly defined immunodeficiency disorders

PID prevalence? JM Boyle & RH Buckley, J. Clin. Immunol. 27:497 (2007) National random probability telephone survey of 10,000 households Reported 23 cases for 27,000 individuals Suggested PID prevalence of 1 in 1,200

Incidence of Primary Immunodeficiencies XLA 1:100,000 SCID 1: 66,000 C22q11 microdeletions 1: 3,000 IgA deficiency 1: 500 Specific antibody deficiencies 1: 500? Overall >1: 500? Polygenic PIDs > monogenic PIDs

Leiva L et al J Clin Immunol 27:101-8, 2007

CLASSIFICATION OF PREDOMINANTLY ANTIBODY-DEFICIENCY SYNDROMES Immunoglobulin deficiencies: Frequency Immunological Severity Clinical Severity X-linked agammaglobulinemia X-linked hyper IgM syndrome Common variable immunodeficiency Transient hypogammaglobulinemia of infancy IgG subclass deficiencies IgA deficiency Specific Antibody deficiencies: Sorensen R, Moore C. Peds Clin NA 47:1225-1252, 2000

Learning Objectives Define Primary Immunodeficiency Diseases (PIDD) Warning signs of a PIDD Evaluation for PIDD Referral recommendations

Variable Natural History of PIDD Many gene defects causing an immunodeficiency do not cause abnormal symptoms Pathology is caused by the infectious, autoimmune, inflammatory or malignant complications

IMMUNOCOMPETENCE Normal immunity Protection against: Infections Inflammation Autoaggression Malignancy Allergy

Clinical Manifestations of PID Allergy Malignancy Skin Disease Periodic Fevers Infections Lymphoproliferation Inflammation Auto- Immunity Gastrointestinal Manifestations

Infections When is an infection suggestive of an immunodeficiency?

10 Warning Signs 17

Adult 10 Warning Signs Poster 18

The Problem with PIDD Warning Signs In many patients with positive warning signs, no immunodeficiency is identified by our present diagnostic methods Some patients with PIDDs reach positive warning signs only after having too many infections

Types of infections: Recurrent infections, multiple pathogens. frequent antibiotic use Severe, even if only one infection Unusual, caused by an infection agent that does not cause infections in most exposed individuals Chronic infection with pathogen that usually causes self-limited infection Inflammation, low or excessive

Types of infections: Recurrent Severe Unusual Chronic

Expected versus Pathologic Recurrent Infections Abnormality defined by Early onset in first months of life Persistence after 3-5 years of age Recurrence after completing antibiotic treatment Severity and complications: Sepsis, pneumonia, mastoiditis, empiema, etc Lack of systemic or local predisposing factors

Recurrent / Chronic Otitis Media When do we suspect an immunodeficiency: Early onset < 3-4 months of age Recurrence after antibiotic treatment Complications: mastoiditis Association with invasive infections Recurrence after ear tubes Change to sinusitis after ear tubes Repeated ear tube placement

Immunization status When pathogen is known Is the patient immunized against the infecting pathogen? When the pathogen(s) are not known Is the patient fully immunized?

Treatment and Response to Treatment Was the treatment appropriate? Did the patient respond to antibiotic treatment? Did the patient do better with antihistamines? Steroids and anti-inflammatories help most conditions, at least transiently

Recurrent / Chronic Otitis Media Predisposing causes: Anatomic abnormalities Eustachian tube dysfunction Pacifier use Bottle feeding Smoke exposure Chronic rhinitis / allergic rhinitis Immunodeficiency

Physical examination: Allergic shiners Purulent nasal secretion Cervical lymph nodes: not palpable Tonsils were not visible

When is an Infection Suggestive af a PIDD? When the infection phenotype does not match the known pathogenicity of an infectious agent

PIDD Infection Summary Every recurrent, unusual or severe infection.

PIDD Infection Summary occurs in a susceptible person that could have a primary immunodeficiency Identifying the cause helps prevention and treatment

Recommendation for Infectious Disease Specialists Identification which is the infection pathogen and its susceptibility to antibiotics is important, but. consideration of why a given pathogen caused disease in a specific patient is also important.

Family History Evaluate when negative: patient is the only one getting sick rules out environmental or social factors Evaluate when positive for PIDD in: Symptomatic family members Asymptomatic, genetically susceptible family members

PIDD Inheritance forms Autosomal dominant Autosomal recessive X-linked diseases (frequent) New mutations (sporadic cases) Maternal carrier Multifactorial, low penetrance

XY CLASSIC PHENOTYPE VARIANT PHENOTYPE

Learning Objectives Define Primary Immunodeficiency Diseases (PIDD) Warning signs of a PIDD Evaluation for PIDD Referral recommendations

B cells/ Antibodies Complement Otitis media, Mastoiditis Maxillary sinusitis, Acute, chronic bronchitis. Bacterial pneumonia, Klebsiella pneumonia Hemophilus pneumonia Broncho-pneumonia, Pnemococcal sepsis Giardiasis Staph Thrush Mycoses Lymphopenia Mycobacteria infection MAC, Herpes Zoster T cells Empyema Cellulitis Bacterial meningitis Aseptic meningitis Viral Infections Osteomyelitis Fungal Infections Deep abscesses Neutrophils

Phenotype / Molecular / Genotype Diagnosis of Primary Immunodeficiencies MOLECULAR ABNORMALITY PROTEIN IMMUNE PHENOTYPE CLINICAL PHENOTYPE Sequencing: Genes Gene panels Exome Genome Receptors Enzymes Cytokines Presence Function Neutrophils Complement Antibodies Lymphocytes Innate immunity Infection Inflammation Autoimmunity Protein-based and functional assays

Pathogen, Infection Phenotype and PIDD Increasing knowledge about: Pathogen and infection phenotype and susceptibility factors including PIDDs: Frequent PIDDs Rare PIDDs related to that phenotype Very unlikely PIDDs

Pathogen, Infection Phenotype and PIDD, ctd Increasing knowledge about: Specific Immunodeficiency and infection pathogen and phenotype Multiple pathogens, multiple infections Susceptibility to specific pathogens

Phenotype / Molecular / Genotype Diagnosis of Primary Immunodeficiencies MOLECULAR ABNORMALITY PROTEIN IMMUNE PHENOTYPE CLINICAL PHENOTYPE Sequencing: Genes Gene panels Exome Genome Receptors Enzymes Cytokines Presence Function Neutrophils Complement Antibodies Lymphocytes Innate immunity Aggressively identify pathogen Inflammation Autoimmunity Protein-based and functional assays

Pathogen, Infection Phenotype and PIDD Examples based on type of PIDD and infection phenotypes

Infections and Antibody Deficiencies Clinical presentation (mostly after 6 mo of age): Recurrent upper and/or lower respiratory infections Severe or recurrent invasive infections Bronchiectasis Chronic diarrhea Very frequent antibiotic use with transient improvement

Infections and Antibody Deficiencies Pathogens common to all deficiencies: Streptococcus pneumoniae Branhamella catarrhalis Haemophilus influenzae (type b and non typable) Staphylococcus aureus Mycoplasma pneumoniae Viruses

Infections and Antibody Deficiencies Pathogens seen in XLA (Btk mutation): Meningoencephalitis due to chronic enteroviral infections (Echoviruses, Coxsackie, rarely poliovirus) Skin necrosis with muscle and bone infection caused by Echoviruses, chronic helicobacter or mycobacterial infections.

Immunodeficiencies and S. pneumoniae infections Recurrent Invasive mucosal Ig defs (Multiple) +++ + SAD polysacch. +++ + SAD conjugate +++ + Complement defs + + Asplenia - +++ IRAK mutation? +++ NEMO mutation? +++

Infections in Chronic Granulomatous Diseases Susceptibility to catalase- positive pathogens: S. aureus, Aspergillus spp, enterobacteriaceae, mycobacteria causing suppurative lymphadenitis, pneumonitis, osteomyelitis, liver abscesses Serratia marcescens Chromobacterium violaceum Burkholderia cepacia Torulopsis glabrata Francisella philomiragia Granulibacter bethesdensis

Phenotype / Molecular / Genotype Diagnosis of Primary Immunodeficiencies MOLECULAR ABNORMALITY PROTEIN IMMUNE PHENOTYPE CLINICAL PHENOTYPE Sequencing: Genes Gene panels Exome Genome Presence, Function Flow cytometry Neutrophils Complement Antibodies Lymphocytes Innate immunity Infection Inflammation Autoimmunity

Learning Objectives Define Primary Immunodeficiency Diseases (PIDD) Warning signs of a PIDD Evaluation for PIDD Referral recommendations

How can Immunologists Help? Immunologists are trained in the diagnosis and management of primary immunodeficiency How to diagnose symptomatic patients and presymptomatic family members When/if to vaccinate which vaccines Prophylactic therapies specific to diagnosis Decisions about immunologic reconstitution Genetic counseling and family evaluation Management of immunoglobulin replacement Co-management with the medical home is key to success

Jeffrey Modell Diagnostic Center for Primary Immunodeficiencies, New Orleans www.jmcenterneworleans.org ConsultJMCNOLA@gmail.com Kenneth Paris, M.D. Victoria Dimitriades, M.D. Luke Wall, M.D. Augusto Ochoa, M.D. Lily Leiva Ph.D. Ricardo Sorensen, M.D.