Evaluation And Treatment Of Immune Deficiency In Adults

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Evaluation and Treatment ofImmune Deficiency in AdultsTolly Epstein, MD, MSAdjunct Assistant Professor of Clinical MedicineDivision of Immunology, Allergy, & Rheumatology2013 Ohio ACP Scientific Meeting

Disclosures None

Learning Objectives#1: Identify clinical findings that warrant furtherinvestigation for primary or secondary immunedeficiency in adults.#2: Formulate a differential diagnosis for suspectedimmune deficiency in adults, and initiate appropriatetesting and sub-specialty referral.#3: Summarize evidence-based treatment algorithmsfor immune deficiency in adults, and gain expertiseregarding the risks and benefits of treatment.

Case 70 year old female admitted to Universityof Cincinnati Hospital with fever, fatigue,cough– Found to have left upper lobe pneumonia onchest X-ray– Blood cultures positive for S. pneumococcus– Improving with IV antibiotics, ready to gohome, but the resident notices that the patienthas been admitted several times forpneumonia in the past

Case #1 Further history and review of records reveals 11lobar pneumonias in the last 20 years– Also at least 5-6 episodes of sinusitis per year, andear pain– Minimal infectious history prior to age 50 Non-smoker No history of environmental allergies No lymphadenopathy on exam, no chronic nightsweats or weight loss Outpatient pulmonary function tests were normal1 and 3 years ago

An impairment in what type of immuneresponse is most likely in an adultpresenting with recurrent lobar pneumonias,sinusitis, and/or otitis media?A. Cell-mediatedimmunityB. Humoral immunityC. Combinedimmunity (both cellmediated andhumoral)D. Innate immunity25%A.25%25%B.C.25%D.

Brief Review of the Immune SystemPMNMacrophageAbbas Cellular & Molecular Immunology 2012Innate immunity provides initial defense against infections.Adaptive immunity develops later and involves greater specificity in terms of recognition andresponse.

Humoral versus Cell-mediated ImmunityCD4CD8Abbas Cellular & Molecular Immunology 2012

Cellular Immunity is also important forHumoral response to protein antigensAbbas Cellular & Molecular Immunology 2012

Pathogens associated with Deficienciesof Innate Immune SystemType of immune deficiency Pathogens involvedNeutropenia/Phagocytic cell deficienciese.g. Chronic Granulomatous DiseaseStaph aureus, Coag negativeStaph, oral Streptococci,Enterococcus, Enterobacteriacea,Pseudomonas aeruginosa,Candida, AspergillusComplement deficiencyNeisseria species (need membraneattack complex),Strep pneumococcusNK cell deficiencyViral infections, particularly herpesviruses

Pathogens associated withDeficiencies of Adaptive Immune SystemType of immune deficiencyPathogens involvedHumoral (B cell/ antibodies)Extracellular: S.pneumococcus, H.influenza, Giardia,CryptospordiumT cell deficiencyIntracellular: includingHerpes simplex virus(HSV), Mycobacterium,Listeria, and intracellularfungi (Histoplasma), P.jirovecii

Back to Case Suspected Humoral immune deficiency– Recurrent pneumonias, sinusitis, otitis media Extracellular, common pathogen (S. pneumococcus)

Categories of Immune Deficiency in Adults1) Secondary immune deficiency due to underlyingdisease, or due to complication of therapy2) Known inherited genetic disorder resulting inprimary immune deficiency that was diagnosedin childhood ( 200 defined so far)3) Late-onset primary immune disorder presentingin adulthood

Secondary Immune Deficiency in Adults Much more common than primary immunedeficiency HIV infection Metabolic disorders– Diabetes (neutrophil dysfunction, cardiovascularcompromise)– Uremia (impaired T,B, and phagocytic cells)– Liver failure (leukopenia, neutropenia due tosplenomegaly with splenic margination)

Secondary Immune Deficiency in Adults Malignancy– Chronic lymphocytic leukemia Abnormal cellular and humoral immune responses Up to 50% die from infection– Lymphoma Generally humoral immune deficiency unless T cells involved– Multiple myeloma May have high IgG but ineffective since mostly from over-producingclone Some may have low B cells and hypogammaglobulinemia– Thymoma with hypogammaglobulinemia, and sometimescellular immune deficiency Good’s syndromeTsiodras Mayo Clin Proc 2000

Secondary immune deficiency in Adults Medications– Immunosuppressives: cytotoxic drugs,glucocorticoids, chemotherapy– Monoclonal antibodies, including Rituximab1– Anti-epileptic drugs Radiation---leukopenia, immune celldysfunction1Cooper,B J Hematology 2009

Secondary Immune Deficiency in Adults Malnutrition, and vitamin/mineral deficiency (Zinc) Protein loss (nephropathy, GI losses, burns) Aging Asplenia---susceptible to polysaccharide encapsulatedbacteria Autoimmune diseases associated with complementconsumption (Systemic Lupus)

Back to our case of suspected humoralimmune deficiency in an adult CBC with differential, liver function tests, renalpanel, blood glucose were normal HIV negative, Serum protein electrophoresis(SPEP) and urine protein electrophoresis(UPEP) negative No other signs/symptoms or history consistentwith other causes of secondary immunedeficiencyConsider a primary immune deficiency

Why should we learn about rare diseaseslike primary immune deficiencies? A disease is no longer rare when it affects our lovedones or ourselves Rare diseases often teach us mechanistic lessons thatimpact the evaluation and treatment of common ones Primary immune deficiencies are frequentlyunrecognized in both adults and children– Diagnosis delayed by 12.4 years, on averageSrinivasa Am J Med 2012; Immune Deficiency Foundation 2013

Most Patients with Primary Immunodeficiencyare Diagnosed in Adulthood30-44years62%diagnosed inadulthood!45-64years65 thN 1030 patients on immunoglobulin replacement therapy for primary immunedeficiency; Immune Deficiency Foundation Survey 2008

Primary Immune Deficiency in Adults 1:1200 adults in the US have a primary immunedeficiency– More common among genetically isolated orconsanguineous populations– IgA deficiency most common (1:300-1:600Caucasians), but usually asymptomatic– Common variable immune deficiency (CVID) 1:25,000 Caucasians Most common clinically important primary immunedeficiency in adultsBoyle JACI 2007; Hammarstrom Clin Exp Allergy 2000; Srinavasa Am J Med 2012

Types of Primary Immune DeficiencyDiagnosed in AdulthoodCommon variableimmune deficiencyUndefined or novelhumoral immunedeficiencyT-cell immune deficiency13%58%20%Combined cellular andhumoral immunedeficiencyNatural killer celldeficiencyPhagocytic deficiencyn 210 patients diagnosed with primary immune deficiency in adulthood;Srinavasa Am J Med 2012Excludes IgA deficiency

Which of the following are the mostappropriate initial tests for suspectedhumoral immune deficiency, as in ourCase?A) Lymphocytesubpopulation studiesB) Quantitative IgG, IgM,and IgA subclassesC) Total IgE levelD) Quantitative IgG, IgM,and IgA levels (total)25%125%225%325%4

Case - Initial testing Total IgG 22 (normal 602-1406) Total IgM 20 (normal 63-263) Total IgA 7 (normal 48-345) Lymphocyte subpopulation studies werenormal– Normal T, B and NK cell numbers– Normal CD4/CD8 ratio

In a stable patient with low immunoglobulins,a normal CBC, and recurrent infections, themost appropriate next step is to:A) Begin Immunoglobulinreplacement therapy (IVIG)B) Perform bone marrowbiopsyC) Check specific vaccinetitersD) Begin prophylacticantibiotics25%125%25%2325%4

Diagnostic Criteria forCommon Variable Immune Deficiency (CVID) IgG levels 2 standard deviations below the mean Most patients have low IgA, and many have low IgM ***Must document impaired production of specificantibodies surrogate functional study***– Isohemagglutinins IgM antibodies against blood cellantigens– Poor responses to one or more vaccines T cell abnormalities are not uncommonCunningham-Rundles Hematology 2012Bonilla JACI 2005

Evaluating response to vaccines in adults1) Check IgG to Pneumococcus– Polysaccharide antigen (T cell independent)Check IgG to Diphtheria and Tetanus– Protein antigens (T cell dependent)2) Vaccinate with pneumococcus (PPV-23);vaccinate with tetanus and diphtheria if lowtiters3) Repeat vaccine titers 4-8 weeks later-For ages 6-65 years, a normal response to PPV conversion of 70% of serotypes tested with 2-4fold increase in titersMay see less response in adults 65 yearsCunningham-Rundles Hematology 2012Orange JACI 2012

Case - Diagnosis Inadequate response to pneumococcus,tetanus, and diphtheria vaccines Diagnosis CVID

At what age are mostindividuals with CVIDdiagnosed?(A) Less than age 1 year(B) Ages 1-4 years(C) Ages 4-20 years(D) Ages 20-40 years(E) Greater than age 40years20%120%20%2320%420%5

Molecular basis for CVID Largely unknown– Likely many different diseases grouped together Rare autosomal-recessive mutations in B-cellfunction genes 8-10% have mutations in B-cell receptortransmembrane activator and calcium-modulatingcyclophilin ligand interactor (TACI)– Can see same mutations in non-immunodeficientindividualsCunningham-Rundles Hematology 2012

Pathologic hallmarks of CVID A relative or complete loss of plasma cellsin the bone marrow and other tissues suchas the lamina propria of the GI tract Generally have normal total B cell count,but reduced numbers of isotype switchedmemory B cells (IgG-IgM-CD27 )Cunningham-Rundles Hematology 2012

Which of the following are not typicallyconsidered manifestations of CVID?(A) Noncaseatinggranulomatous lungdisease(B) Disseminatedhistoplasmosis(C) Chronic diarrhea andmalabsorption(D) Lymphoma(E) Thrombocytopenia20%120%20%2320%420%5

Percent of PatientsManifestations of CVID3530N 473 patients followed for 4 years2520151050Resnick, Blood 2012

Morbidity/Mortality from CVID Most patients with CVID do not die from infections, ifthey are treated with immune globulin replacementNon-infectiouscomplications versus nocomplications; P .0001 Most common cause of death Autoimmune conditionsor Malignancy (54% lymphoma)Resnick Blood 2012; Cunningham-Rundles Hematology 2012

Autoimmune conditions in CVIDIdiopathicthrombocytopeniapurpura (ITP)Autoimmune hemolyticanemia (AIHA)3%5%10%Evans syndrome (ITP AIHA)44%13%Rheumatoid arthritisAnti-IgA antibody22%AlopeciaOthersResnick Blood 2012

Treatment ImmunoglobulinReplacement Therapy Pooled immunoglobulin (95% IgG) from 1,000donors Treat to patient’s “biological” IgG level– Evidence that IgG 800 is generally better thanIgG 500Bonagura JCI 2012

FDA approved indications for IVIG Allogeneic bone marrow transplantChronic lymphocytic leukemia (CLL)Primary immune deficienciesIdiopathic thrombocytopenic purpura (ITP)Pediatric HIVKawasaki diseaseChronic inflammatory demyelinatingpolyneuropathy (CIDP) Kidney transplant with a high antibody recipient orABO incompatible donor

Potential adverse effects of ImmuneGlobulin Replacement Therapy Most common HeadachesAseptic /renal failure (much lower withlower osmotic and low sucrosepreparations) Dermatitis Venous thrombosisBonagura JCI 2012

Potential adverse effects of ImmuneGlobulin Replacement Therapy Viral infection (HCV, HBV, HIV) Anaphylaxis in IgA deficient patients Infusion related and Anaphylactoidreactions (due to immune precipitates)– 5-14% of patients on IVIG– Pre-medication can help

IV vs SubQ Immunoglobulin TherapyIntravenous (IVIG) Advantages:– Rapid peak for severely ill– Dose every 4 weeks Disadvantages:Subcutaneous (SCIG) Advantages:––––Stable IgG levelPatients can infuse themselvesLower risk of severe reactionsDoes not require IV access– Rapid loss of IgG after infusionwith GI or renal losses Disadvantages:– Less efficacious at trough level– Must be given 1X per week– Greater potential for severe– High risk of local infusion siteadverse eventsreactions (up to 49%)– Need highly motivated patientBonagura JCI 2012; Moore Ann of Allergy 2008

Resolution- Case Patient started IVIG q month, ultimatelytransitioned to SubQ immunoglobulinreplacement due to convenience Tolerated very well with no re-admissionsand minimal infections

6 Warning Signs for Immune Deficiencyin an Adult(1) 4 infections requiring antibiotics within 1 year(2) Recurring infections or infection requiring prolongedantibiotic therapy(3) 2 severe bacterial infections (osteomyelitis,meningitis, septicemia, cellulitis)European Society for Immunodeficiencies 2013

6 Warning Signs for Immune Deficiencyin an Adult(4) Two or more radiologically provenpneumonias within 3 years(5) Infection with unusual localization orunusual pathogen(6) Primary immune deficiency in the family-Early deaths, consanguinity, autoimmune diseaseEuropean Society for Immunodeficiencies 2013

Non-infectious clues toImmune Deficiency 6% of patients with primary immunedeficiency do not present with infections Premature loss of dentitionRecurrent aphthous ulcersPoor/delayed wound healingMultiple autoimmune disordersExtensive skin wartsChronic diarrheaBronchiectasisImmune Deficiency Foundation Survey 2008

Summary Suspect immune deficiency in patients with:– Recurrent or persistent infections– Infections from unusual or less virulent infectiousagents– Low blood cell counts Secondary immune deficiency is morecommon in adults, but the majority of patientswith primary immune deficiency arediagnosed in adulthood

Summary Consider pathogen and most likely component of theimmune system (innate versus adaptive, humoralversus cellular) when initiating work-up Functional studies (vaccine responses) should beconducted prior to making a diagnosis of and initiatingtreatment for a suspected humoral immune deficiency Most primary immune deficiencies in adults can bemanaged with favorable outcomes, but frequentlyrequire life-long replacement therapy

Thank you! What questions do you have?

impact the evaluation and treatment of common ones Primary immune deficiencies are frequently unrecognized in both adults and children –Diagnosis delayed by 12.4 years, on average Srinivasa Am J Med 2012; Immune Deficiency Foundation 2013 . Most Patients with Primary Immunodeficiency

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