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

T cell deficiencies Fungi Viruses Pneumocystis

B-cell deficiencies S. pneumococcus H.influenzae Enteroviruses

Complement deficiencies Bacteremia Meningitis C5-9: Neisseria C1/2/4: SLE

Phagocytic disorders Staph skin infections Cepacia Infections of the

reticuloendothelial system Abscesses

The type of infectious agent and the location of the infection may give valuable insight into the nature of the immunologic defect. . .

Humoral Immunodeficiencies

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

DifferentialHumoral immune

deficiencyCFPrimary Ciliary

Dyskinesia

Differential for Humoral Immune Deficiency in Adults Drugs

Antimalarials, captopril, carbamazepine, steroids, gold, penicillamine, phenytoin, sulfasalazine

Systemic disorders Chronic medical

conditions CF Sickle Cell

Hypercatabolism of Ig Excessive loss of Ig

Nephrosis, burns, diarrhea, lymphangiectasia

ID HIV, EBV

Malignancy 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 receptorsTACI 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)

TACI-deficient mice show ↑ B cells, impaired isotype switching and develop autoimmune manifestations with (SLE)-like symptoms, lymphoproliferation,splenomegaly, and lymphoma

Bacchelli et al. Clin Exp Immunol 2007; 149:1365-2249

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 triggersViral infectionDrugs

Antimalarials, captopril, carbamazepine, steroids, gold, penicillamine, phenytoin, sulfasalazine

CVID: Clinical Manifestations

Infectious DiseaseRecurrent pyogenic sinopulmonary infectionsChronic enteroviral infectionsMeningoencephalitisChronic Giardia LambliaRecurrent HSV and/or VZV

CVID: Clinical Manifestations

GI manifestationsSprue-like syndrome (wt loss, diarrhea, vitamin

deficiency, hypoalbuminemia)Nodular follicular hyperplasia of the

intestinesGastric atrophy, achlorydriaColitisMALT lymphomaGiardiasis

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 manifestationsGranulomatous disease

Noncaseating epithelioid granulomas of liver, lung, spleen, skin, gut

AmyloidosisTonsilar tissue normal or enlargedLymphadenopathy25% splenomegaly

CVID: Clinical Manifestations

Malignancy300+ fold increase in lymphomas in women

between 50-60 yo50 fold increase in gastric carcinomaThymomaMALT lymphomaLymphoreticular malignancy

CVID: Clinical Manifestations

Pulmonary manifestationsPneumoniaAsthmaBronchiectasisLymphoid 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 Pneumococcal polysaccharide HIB polysaccharide Tetnus toxoid

Measurement of quantitative Ag-specific Ig titer pre- and post-immunization 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-immunization4 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 Gammagard-SD, Polygam-SD: IgA def patients

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) 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 affectedAsymptomaticRecurrent infections: sinopulmonary, diarrhea

Selective IgA deficiency

Higher incidence of autoimmunityRASLE ITP

AtopyAsthmaFood allergy

Selective IgA Deficiency

TreatmentSupportive

Risk of anaphylaxis to blood productsFormation 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): 696-707.

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: 1099-1103.

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.