Case Presentation - UNC School of Medicine
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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
S. pneumococcus
H.influenzae
Enteroviruses
Phagocytic disorders
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
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
Targetted H&P for recurrent infections and
autoimmunity
Quantitative serum Ig (age and sex matched
controls)
Measurement of Ab production
Measurement of quantitative Ag-specific Ig titer
pre- and post-immunization
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
Treatment of CVID
IVIG
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
Preparations with high titer specific IG against
infectious pathogens
Cytogam: High titered IVIG for CMV
Respigam: High titered IVIG for RSV
Increased toxicity with live virus vaccines (MMR)
Gammagard-SD, Polygam-SD: IgA def patients
Do not administer within 3 months of vaccination
T ½ 15-30 days
Side Effects of IVIG
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
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
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
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.