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Diagnosis and Management
of Immunodeficiency in Adulthood
Teresa Tarrant, MD
Assistant Professor of Medicine
Division of Rheumatology, Allergy, and Immunology
The Immune System:
http://stemcells.nih.gov/info/scireport/chapter6.asp
Pattern of infections:
Clinical Immunology
The type of infectious agent and the location of the infection may give valuable
insight into the nature of the immunologic defect. . .

T cell deficiencies
Complement deficiencies
Fungi
Viruses
Pneumocystis

B-cell deficiencies

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




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
S. pneumococcus
H.influenzae
Enteroviruses
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Phagocytic disorders

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
Humoral Immunodeficiencies
Bacteremia
Meningitis
C5-9: Neisseria
C1/2/4: SLE

Staph skin infections
Cepacia
Infections of the
reticuloendothelial system
Abscesses
Clinical Scenario:
Recurrent infections

32 yo previously
healthy female who
has a 3 year history of
sinus drainage and
recurrent sinus
infections. . .

Differential:
Allergies
 Chronic sinusitis
 Allergic fungal sinusitis
 Antibiotic resistance
 Mechanical
derangement

Clinical Scenario:
Recurrent infections

32 yo previously
healthy female who
has a 3 year history of
sinus drainage,
recurrent sinus
infections, who
developed bilateral
otitis media requiring
tympanostomy and IV
antibiotics. . . .

Differential
Allergies
 Chronic sinusitis
 Allergic fungal sinusitis
 Antibiotic resistance
 Mechanical derangement
 Humoral immune
deficiency
 CF
 Primary Ciliary Dyskinesia

Clinical Scenario:
Recurrent infections

Now it’s the same
32 yo female . . .
who develops
fevers, increased
sputum, and an
infiltrate seen on
CXR

Differential
 Humoral
immune
deficiency
 CF
 Primary Ciliary
Dyskinesia
Differential for Humoral Immune
Deficiency in Adults

Drugs


Antimalarials, captopril,
carbamazepine, steroids,
gold, penicillamine,
phenytoin, sulfasalazine

ID


Malignancy


Systemic disorders
 Chronic
medical
conditions



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CF
Sickle Cell
Hypercatabolism of Ig
Excessive loss of Ig

Nephrosis, burns, diarrhea,
lymphangiectasia




HIV, EBV
CLL
Immunodeficiency with
thymoma (Good’s
syndrome)
NHL
CVID
IgA deficiency
IgG Subclass
deficiency
Common Variable
Immunodeficiency


Definition: a disease characterized by
low levels of immunoglobulins and
recurrent sinopulmonary infections.
It is a relatively common
immunodeficiency with variable levels of
immunoglobulins and clinical course
between patients
CVID


Heterogeneous group of disorders of humoral
immunodeficiency with associated bacterial
infections, autoimmune disease, and
malignancy
Bimodal distribution
 Major
peak 25-45 yo
 Second peak 5-15 yo


M=F
Prevalence estimated at 1:25,000-50,000
CVID: Pathogenesis
 Some molecular defects identified
 TACI mutation (~20% of CVID)
 Most cases are sporadic
 Familial inheritance has been
demonstrated
□ X-linked
□ Autosomal recessive
□ Autosomal dominant
CVID: Genetic

Mutations in the genes encoding the tumor
necrosis factor (TNF) superfamily receptors
 TACI

mutation
Transmembrane activator and calcium-modulating
ligand interactor
 BAFF-R


mutation
B cell activation factor of the TNF family receptor
Small number of patients with CD19
deficiency
TACI mutation


TACI is expressed on
the surface of B cells
TACI interacts with
 BAFF
(activation factor)
 APRIL (proliferation
ligand)
Bacchelli et al. Clin Exp Immunol 2007; 149:1365-2249

TACI-deficient mice show ↑ B cells, impaired
isotype switching and develop autoimmune
manifestations with (SLE)-like symptoms,
lymphoproliferation,splenomegaly, and lymphoma
CVID: Pathogenesis

Familial inheritance
 IgA deficiency
Kindreds with IgA deficiency and CVID
 15% of patients with CVID have a first degree
relative with IgA deficiency
 Individuals with IgA deficiency who develop
CVID

 MHC
haplotypes shown to correlate with
CVID and IgA deficiency
CVID: Pathogenesis
 Environmental
triggers
 Viral
infection
 Drugs

Antimalarials, captopril, carbamazepine,
steroids, gold, penicillamine, phenytoin,
sulfasalazine
CVID: Clinical Manifestations

Infectious Disease
 Recurrent
pyogenic sinopulmonary infections
 Chronic enteroviral infections
 Meningoencephalitis
 Chronic Giardia Lamblia
 Recurrent HSV and/or VZV
CVID: Clinical Manifestations

GI manifestations
 Sprue-like
syndrome (wt loss, diarrhea, vitamin
deficiency, hypoalbuminemia)
 Nodular
follicular hyperplasia of the
intestines
 Gastric atrophy, achlorydria
 Colitis
 MALT lymphoma
 Giardiasis
Nodular Lymphoid Hyperplasia of
the Duodenum
Nodules develop through lymphocyte proliferation in the lamina propria
and submucosa, but are not directly linked to increased malignant
potential.
CVID: Clinical Manifestations

Autoimmune manifestations (22-50%)
 Pernicious
anemia
 Vitiligo
 Autoimmune
thrombocytopenia
 Autoimmune hemolytic anemia
 Autoimmune thyroiditis
 Alopecia areata
 Keratoconjunctivitis sicca
 Inflammatory Arthritis
CVID: Clinical Manifestations

Hematologic manifestations
 Granulomatous

disease
Noncaseating epithelioid granulomas of liver, lung,
spleen, skin, gut
Amyloidosis
 Tonsilar tissue normal or enlarged
 Lymphadenopathy
 25% splenomegaly

CVID: Clinical Manifestations

Malignancy
 300+
fold increase in lymphomas in women
between 50-60 yo
 50 fold increase in gastric carcinoma
 Thymoma
 MALT lymphoma
 Lymphoreticular malignancy
CVID: Clinical Manifestations

Pulmonary manifestations
 Pneumonia
 Asthma
 Bronchiectasis
 Lymphoid
interstitial pneumonia (LIP)
 Pulmonary Fibrosis
Best predictor of improved pulmonary outcome is
early diagnosis and aggressive treatment.
J. de Gracia, et al., Int Immunopharmacol 4 (2004), 745–753.
Laboratory evaluation of Humoral
Immune Deficiency
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Targetted H&P for recurrent infections and
autoimmunity
Quantitative serum Ig (age and sex matched
controls)
Measurement of Ab production
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Measurement of quantitative Ag-specific Ig titer
pre- and post-immunization

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Pneumococcal polysaccharide
HIB polysaccharide
Tetnus toxoid
4 week post-immunization level within protective range and
>4 fold rise from baseline
Peripheral blood lymphocyte subset analysis
Quality not Quantity

Measurement of Antigen-specific (i.e.
tetanus, HIB, pneumococcal) IgG titer
pre- and post-immunization
4
week post-immunization level within
protective range and/or >4 fold rise from
baseline
Immunoglobulin Defects
<2 SD below the mean in IgG and
another Ig class or <5th percentile of
total IgG for a given age
 Poor or absent response to
immunization

 <Two-fold
increase in Ag-specific titer
CVID: Clinical Surveillance
PFT’s
 High resolution CT of the chest to evaluate
for bronchiectasis
 Stool O&P, bacterial cx, C. difficile for
changes in GI sx
 CBC q6 mo for autoimmune cytopenias
 Low threshold for lymphoma
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Treatment of CVID
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IVIG
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Higher doses to keep trough IgG levels >500 mg/dl decreases
infections, hospitalizations, need for abx therapy and improves
pulmonary function
0.2-0.6 g/kg/mo or 300-500 mg/kg/q2-4 weeks IV
IV and subcutaneous routes equally effective
Pre-existing chronic lung disease is not improved by IVIG
Stiehm, E et al. Pediatr Infect Dis J, 1997. 16 (7): 696-707.
IVIG


First licensed in 1981 for primary antibody
deficiencies as an improved, less painful
alternative to IM injections of IG
Subtle differences in Ab titers, IgA depletion, and
IgG subclass that vary between lots as well as
manufacturers

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Preparations with high titer specific IG against
infectious pathogens
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Cytogam: High titered IVIG for CMV
Respigam: High titered IVIG for RSV
Increased toxicity with live virus vaccines (MMR)

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Gammagard-SD, Polygam-SD: IgA def patients
Do not administer within 3 months of vaccination
T ½ 15-30 days
Side Effects of IVIG
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Mild side effects occur in approximately 10% of infusions
Side effects often preventable with ASA (15 mg/kg/dose) or
acetominophen (15 mg/kg/dose) with diphenhydramine
(1mg/kg/dose).
Occasionally, hydrocortisone (6mg/kg/dose, max=100mg) 1hr
prior
Stiehm, E et al. Pediatr Infect Dis J, 1997. 16 (7): 696-707.
Infectious Disease Transmission with
IVIG

Hepatitis C has been reported after
administration of certain lots of IVIG
 Cases
appeared after Hep C Ab+ patients were
excluded as donors
 Hypothesis is that Hep C Ab neutralizes virus in
donor pools
 Consequently new pasteurization +/solvent/detergent processing and testing for HCV
RNA to reduce viral transmission

Several IVIG lots were recalled after donors
developed Creutzfeldt-Jakob disease
 No

cases were reported of CJD transmission
No cases have been reported of HIV
transmission
Subcutaneous IgG (Vivaglobulin)


Ochs HD et al; Subcutaneous IgG Study Group.
Safety and efficacy of self-administered
subcutaneous immunoglobulin in patients with
primary immunodeficiency diseases.
J Clin Immunol. 2006 May;26(3):265-73.
Moller G et al: Subcutaneous immunoglobulin
replacement in patients with primary antibody
deficiencies: safety and costs. Lancet. 1995 Feb
11;345(8946):365-9.
Selective IgA deficiency
Severe deficiency or total absence of the
IgA class of immunoglobulins
 Estimated prevalence 1:500-1:1000
persons
 Spectrum of clinically affected

 Asymptomatic
 Recurrent
infections: sinopulmonary, diarrhea
Selective IgA deficiency
 Higher
incidence of autoimmunity
 RA
 SLE
 ITP
 Atopy
 Asthma
 Food
allergy
Selective IgA Deficiency

Treatment
 Supportive

Risk of anaphylaxis to blood products
 Formation

of IgG or IgE anti-IgA antibodies
Subset with IgG2 subclass deficiency
IgG Subclass Deficiency

The IgG class of antibodies is composed
of four different subtypes of IgG molecules
 IgG1,

IgG2, IgG3, and IgG4
Patients who lack, or have very low levels
of, one or two IgG subclasses, but whose
other immunoglobulin levels are normal,
are said to have a selective IgG subclass
deficiency.
IgG Subclass Deficiency

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
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The clinical significance of abnormal IgG subclass
levels in patients with recurrent infections is unclear
A low level of at least 1 IgG subclass has been found
in approximately 2% of a given population, and
Impaired antibody production may not be seen among
adult patients with IgG3 subclass deficiency
A low level of 1 or more IgG subclasses alone is
generally not considered sufficient for a diagnosis of
immunodeficiency
In individuals with recurrent infections and 1 or more
low levels of IgG subclasses, a demonstrable
impairment in antibody response to vaccination or
natural exposure is considered the most important
determinant of disease
Bonilla F et al, Ann Allergy Asthma Immunol. 2005 May;94(5 Suppl 1):S1-63.
Putting it all together. . .

H&P:
 Pattern

of recurrent infections
Rule out secondary causes of immune
dysfunction
 Medications
 Other chronic diseases
 Protein wasting states

Laboratory assessment: quality not
quantity.
 Measurement
of antigen-specific Ig titers pre- and
post-immunization
Primary Humoral
Immunodeficiency
Referral to a Clinical Immunologist
 IVIG or SQ Ig only where there is
demonstrable impairment in IgG production
of antigen-specific antibody titers (quality
not quantity)
 Supportive antibiotics
 Vaccinations: Prevnar, HIB, influenza
 Surveillance for associated clinical
conditions

Key References



Immune Deficiency Foundation website:
http://www.primaryimmune.org/
Orange JS et al. Use of intravenous immunoglobulin in
human disease: a review of evidence by members of the
Primary Immunodeficiency Committee of the American
Academy of Allergy, Asthma and Immunology. J Allergy
Clin Immunol. 2006 Apr;117(4 Suppl):S525-53.
Bonilla F et al. Practice parameter for the diagnosis and
management of primary immunodeficiency. Ann Allergy
Asthma Immunol. 2005 May;94(5 Suppl 1):S1-63.
Additional References
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Conley, ME et al. Diagnostic criteria for primary immunodeficiencies.
Clin Immunol 1999. 93 (3): 190-7.
Stiehm, E et al. Human intravenous immunoglobulin in primary and
secondary antibody deficiencies. Pediatr Infect Dis J, 1997. 16 (7): 696707.
Spickett, GP et al. Common variable immunodeficiency: how many
diseases? Immunol Today, 1997. 18 (7): 325-8.
Rosen, FS et al. Medical progress: the primary immunodeficiencies.
NEJM 1995. 333 (7): 431-40.
Spickett, GP. Current persepctives on common variable
immunodeficiency (CVID). Clin & Exper Immunol 2001. 31 (4): 536-42.
Middleton, E (ed) et al. Allergy Principles and Practice. 5th Ed. Mosby
1998. 724-5.
Ballow, M. Primary immunodeficiency disorders: antibody deficiency.
Curr Rev Allergy and Clin Immunol 2002. 109 (4): 581-91.
Bacchelli et al. Clin Exp Immunol 2007; 149:1365-2249.
Additional References
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Cunningham-Rundles, C et al. Common variable immunodeficiency: clinical
and immunological features of 248 patients. Clin Immunol 1999. 92: 34-48.
Sweinberg SK et al. Retrospective analysis of the incidence of pulmonary
disease in hypogammaglobulinemia. J Allergy and Clin Immunol 1991. 88
(1) 96-104.
Buckley, RH et al. The use of intravenous immne globulin in
immunodeficiency diseases. NEJM 1991. 325 (2): 110-116.
Punnonen, J et al. IL-4 synergizes with IL-10 and anti-CD40 MoAbs to
induce B-cell differentiation in patients with common variable
immunodeficiency. Scand J Immunol 1997. 45: 203-12.
Farrington, M et al. CD40 ligand expression is defective in a subset of
patients with common variable immunodeficiency. PNAS 1994. 91: 10991103.
Schaffer, FM et al. Individuals with IgA deficiency and common variable
immunodeficiency shar polymorphisms of major histocompatibility complex
class III genes. PNAS 1989. 86: 8015-9.
Massimo, M et al. Alterations of the X-linked lymphoproliferative disease
gene SH2D1A in common variable immunodeficiency. Blood 2001. 98 (5):
1321-5.