When (and How) Should I Evaluate My Patient for Immunodeficiency?

When (and How) Should I Evaluate
My Patient for Immunodeficiency?
Workshop
Update in Infectious Diseases
April 27, 2012
Antoine E. Azar, M.D.
Division of Immunology
University of Iowa Hospitals and Clinics
Take Home Points!
Primary Immunodeficiency (PID):
„
Is not rare
„
May present at any age
„
Does not always present with severe infections
„
Early diagnosis and treatment are essential in
order to avoid significant morbidity and
mortality
Outline
1. Outline of the Immune System
2. Overview of Primary Immunodeficiency
3. When to Evaluate for Immunodeficiency
4. How to Evaluate for Immunodeficiency
Outline
1. Outline of the Immune System
2. Overview of Primary Immunodeficiency
3. When to Evaluate for Immunodeficiency
4. How to Evaluate for Immunodeficiency
The Players in the Immune system
„ Innate Immunity
„ Adaptive Immunity
Innate Immunity
„
Epithelial Barriers
„
Phagocytic cells
„
„
Mononuclear phagocytes
Neutrophils
„
Natural Killer (NK) cells
„
Complement
„
Cell Receptors
„
e.g. Toll-like receptors
Receptors of Innate Immunity
Toll Like
receptors
„
„
“Pattern recognition receptors” (PRRs) recognize components
specific to certain microbes
Toll-like receptors (TLRs) are transmembrane PRRs found on and
within cells of the innate immune system
Adaptive Immunity
„
B lymphocytes
Antibodies
Humoral
Helper
CD4+
„
Regulatory
T reg
T lymphocytes
Cellular
Th1,Th2,Th17
CD8+
Cytotoxic
IgM
IgD
Class
Switching
Naive B
IgA
IgE
IgG
Plasma Cells
IgM
IgG
IgA
IgE
„
Helper T cells: TH1 vs TH2
„
e.g. Mycobacterium leprae
Tuberculoid
leprosy
Granulomas
Lepromatous
TH2
leprosy
Destructive
lesions
TH1
CD4
ƒ Specificity
ƒ Memory
Outline
1. Outline of the Immune System
2. Overview of Primary Immunodeficiency
3. When to Evaluate for Immunodeficiency
4. How to Evaluate for Immunodeficiency
Tolerate
“Self”
Eliminate
“Non-Self”
Manifestations of Immunodeficiency
Primary Immunodeficiency (PID)
„
Genetically heterogeneous group of disorders
„
Affect distinct components of the immune
system (innate, adaptive)
„
> 120 responsible genes identified
„
> 150 different forms of PID identified
Primary Immunodeficiency (PID)
„
Prevalence ~ 1:1200 in US
„
„
Boyle JM, Buckley RH.
RH J Clin Immunol. 2007;27(5):497
Selective IgA Deficiency ~ 1:500
„
Most common PID
Modell V. et al. Immunol Res (2011) 51:61–70
Modell V. et al. Immunol Res (2011) 51:61–70
Age at Diagnosis with PID
50%
Immune Deficiency Foundation (IDF) survey 2003, N = 1499
Current Age of Patients with PID
60%
Times Hospitalized Before Diagnosis
IDF survey 2003, N = 1526
Cost Savings After PID diagnosis
„
Modell V. et al. Immunol Res (2011)
51:61–70
Outline
1. Outline of the Immune System
2. Overview of Primary Immunodeficiency
3. When to Evaluate for Immunodeficiency
4. How to Evaluate for Immunodeficiency
Recurrent infections…
“Host”
„
„
„
vs.
Anatomical abnormalities
2ry Immunodeficiency
1ry Immunodeficiency
“Hostility”
„
„
Increased exposure
“Aggressive” organisms
Host factors
„
Anatomical abnormality; e.g.:
„
„
„
„
Pneumonia: bronchial obstruction; aspiration;
Cystic fibrosis
UTI: urinary tract obstruction; stones/tumors;
reflux; neurogenic bladder
Cellulitis: lymphedema, venous insufficiency;
scarring from prior cellulitis
Immune deficiency
„
„
Secondary
Primary
When to Suspect an Immunodeficiency?
„ History
„ Family
History
„ Physical
Exam
History of Present Illness
„
Infection history
Site, frequency, complications
„ Hospitalization, ICU stay
„ Treatment
„
„ IV antibiotics?
„ Multiple antibiotics?
„ More than one course of antibiotics?
„
Non-Infectious clues
Premature loss of dentition
„ Recurrent aphthous ulcers
„ Poor/delayed wound healing
„ Multiple autoimmune disorders
„ Extensive skin warts
„ Chronic diarrhea
„ Bronchiectasis
„
Family History
„
Immunodeficiency
Early deaths
„ Recurrent infections
„ Children’s health during the first 6 months
„
„
„
Consanguinity
Autoimmune disorders
„
Rheumatoid arthritis, SLE, pernicious
anemia, ITP, thyroid disease, …
Physical Exam
„
HEENT
„
„
„
„
„
„
Aphthous ulcers, thrush
Tympanic membrane scarring/perforation
Lungs: Crackles, rhonchi
Abdomen: Hepatosplenomegaly
Lymphadenopathy
Skin
„
„
„
Warts; abscesses; onychomycosis
Scars: nature and extent
Joint deformities
How many infections are too many?
1. More than 3 episodes of bacterial sinusitis in one
year, or chronic sinusitis
2. Pneumonia twice over any time period
3. More than 4 ear infections in one year after age 4
4. More than 2 courses of antibiotics per year (adults);
more than 4 per year (children)
5. Any unusually severe infection
6. Infections caused by organisms that do not usually
cause problems in most people at the patient's age
AAAAI, April 2007
“6 Warning Signs for PID in Adults”
1. Four or more infections requiring antibiotics within one
year (otitis, bronchitis, sinusitis, pneumonia)
2. Recurring infections or infection requiring prolonged
antibiotic therapy
3. Two or more severe bacterial infections (osteomyelitis,
meningitis, septicemia, cellulitis)
4. Two or more radiologically proven pneumonia within 3
years
5. Infection with unusual localization or unusual pathogen
6. PID in the family
European Society for Immunodeficiencies (ESID)
When to Suspect an Immunodeficiency?
„ frequency
„ severity
Infections with
UNUSUAL:
„ duration
„ complications
„ organisms
Non-infectious clues
„
Autoimmunity
„
Poor wound healing
„
Premature loss of dentition
„
Unexplained bronchiectasis
„
Chronic diarrhea or malabsorption
„
“Failure to thrive”
Outline
1. Outline of the Immune System
2. Overview of Primary Immunodeficiency
3. When to Evaluate for Immunodeficiency
4. How to Evaluate for Immunodeficiency
„
Document all infections
„
Etiologic organisms (microbiology)
„ Will guide the workup
Imaging (sinusitis, bronchiectasis)
„ Treatment
„ Complications
„
Secondary Immunodeficiency
„
„
„
„
„
„
„
Malnutrition
HIV
Malignancy
Splenectomy
Vitamin and mineral deficiencies
Immunosuppressive drugs
Immunomodulatory agents
„
Rituximab, infliximab, etanercept, adalimumab,
anakinra
Secondary Immunodeficiency (cont’d)
„
Drug-induced hypogammaglobulinemia
„
„
Protein loss
„
„
Nephrotic syndrome, protein-losing enteropathy,
severe burns
Metabolic disease
„
„
Anti-epileptics (e.g. diphenylhydantoin,
carbamazepine, valproate)
Diabetes mellitus, severe liver disease, uremia
Impaired barriers
„
Cystic fibrosis, immotile cilia syndromes, severe
burns
„
Lab Screening for 2ry immunodeficiency
„
CBC with differential and smear
„
Creatinine, liver function tests, blood glucose
„
Total serum protein, albumin
„
Urinalysis
„
HIV (ELISA or PCR)
Lab evaluation of PID
„
Microbiology and clinical picture guide
the workup
Azar A, Ballas Z. Am J Med 2007; 120(9):764-8
Humoral Immunity (B cells)
„
Infections
„
„
„
Complications
„
„
„
„
„
„
Upper and lower respiratory tract - Bacterial
Gastroenteric – Giardia, Campylobacter
Bronchiectasis
Granulomatous disease (lungs, skin, liver, spleen, GI)
Autoimmune disorders (ITP, hemolytic anemia)
Inflammatory bowel disease (Crohn’s, ulcerative colitis)
Malignancy (lymphoma, GI tract)
False negative serologic tests (HAV, HBV, HCV, HIV…)
Humoral Immunity (B cells)
„
X-linked Agammaglobulinemia (XLA)
„
„
Common Variable Immunodeficiency (CVID)
„
„
„
↓ IgG
↓ IgA and/or IgM
Selective IgA deficiency (incidence ~ 1:500)
„
„
„
No B cells, no Immunoglobulins
Undetectable IgA
Normal IgG, IgM
Functional Antibody Deficiency
„
„
Normal Immunoglobulins
Abnormal antibody response to vaccines
Evaluation of Humoral Immunity
Quantity
„IgG, IgA, IgM
„B cell numbers (Flow cytometry)
„
CD19, CD20
* Immunoelectrophoresis is semiquantitative and
should not be used to evaluate antibody deficiency
Evaluation of Humoral Immunity (2)
Function
„Response to immunization
„
„
Polysaccharide: 23-valent Pneumococcal vaccine
„ 4-fold ↑ in titers to > 70% of serotypes
Polypeptide: Tetanus/Diphtheria vaccine
„IgG Isohemagglutinins = naturally occurring Ig
to ABO blood group antigens
„
70% of infants by age 1 have positive isohemagglutinin titers
IgG IgA IgM
Differential Diagnosis
↓
N
• Selective IgA deficiency (IgA undetectable)
• Anti-epileptics
N
• Protein loss (nephrotic syndrome, proteinlosing enteropathy)
• Antibody deficiency with low IgG
N
↓
↓
↓
N-↑
N
↓-N ↓-N
↓
↓
N-↑
↓
• Common variable immunodeficiency (CVID)
• Monoclonal gammopathy
- Waldenstrom, MGUS, multiple myeloma
• Hyper-IgM syndrome
• Monoclonal IgG production
• CVID on IG replacement therapy
Azar A, Ballas Z. Am J Med 2007; 120(9):764-8
Cellular Immunity (T cells)
„
Opportunistic infections
Viruses
„ Fungi
„ Mycobacteria
„
„
Usually severe, early in life
Cellular Immunity (T cells)
„
Quantity
„
T cell numbers (Flow cytometry)
„
„
CD3, CD4, CD8
Function
„
Delayed-Type Hypersensitivity skin testing
„
Tetanus, Candida, PPD
„ ≥ 5 mm
„
In vitro lymphocyte function
„
„
Proliferation: Mitogens, alloantigen, recall antigens
Differentiation: Interleukin-2 secretion
Natural Killer cells
„
Quantity
„
„
NK cell numbers (Flow cytometry)
„ CD3, CD16, CD56
Function
„
Cytotoxic assays in vitro
Phagocytes
„
Bacterial/ fungal infections
Skin
„ Periodontal tissue
„ Lymph nodes
„ Lung
„ Liver
„ Bone
„
Phagocytes
„
Quantity
„
CBC/Differential
„ Multiple time points
„
Function
„
Superoxide generation
„ Dihydrorhodamine assay (DHR)
„
Chemotaxis (neutrophil movement)
Complement
C1 C4
Classical
pathway
C2
C3
Alternative
pathway
C5
C 5,6,7,8,9
MAC (Membrane attack complex)
Complement
„
Total hemolytic complement assay
„
„
Alternative hemolytic complement assay
„
„
CH50
AH50
Individual complement components