Immunodeficiency

Immunodeficiency Carol T Cady, MD/PhD Missoula Medical Conference October 25, 2014

Disclosures none

Overview • Basic Immune System Components • What constitutes an “unusual” infection? • Immunodeficiency subclasses • Primary • Acquired • Iatrogenic • Screening for immunodeficiency • Treatment of immunodeficiency • Treatment of immunodeficiency

Question #1 Recurrent sino-pulmonary infections with encapsulated bacteria (i.e. S pneumonia, H influenza, N meningitidis) in the absence of systemic viral or fungal infections is most likely an: • Antibody deficiency • Skin barrier defect • CD4+ deficiency • Severe combined immune deficiency

Immune system • Barrier protection • Skin and mucosal surfaces • Innate immunity • Natural or native immunity • Innate lymphocytes • Adaptive immunity • T and B cell acquired responses

Barrier Protection • Skin integrity prevents skin infections • Half of those with severe eczema have a mutation in filaggrin, a protein in epithelial cells that maintains the skin barrier • Tobacco smoke impairs barrier function of sinus and lung epithelial tissue • Recurrent sino-pulmonary infections may be a result of smoking

Barrier Protection • Filaggrin deficiency From: The Scientist, The Allergy Gene by W. H. Irwin McLean | December 1, 2010

Adaptive Immunity • T cells • Helper cells • Cytotoxic cells • Regulatory cells • B cells • IgM • IgA • IgG • IgE Figure from: http://quest.mda.org/article/new-directions

B Cell Antibodies IgM - Pentamer found mostly in serum - Increases early in infection - Combines with complement, to opsonize bacteria • IgA • Produced in mucosal linings • Some in serum (IgA1>IgA2) • Constitutes 75% of Ig’s made • IgE • Parasite defense • Hypersensitivity • Located free in serum • Bound to mast cells/basophils • IgG • Constitutes 75% of Ig’s in serum • Four subtypes IgG1, IgG2, IgG3, IgG4 • IgG1, IgG3 help internalize antigens • Can be either pro-inflammatory or anti- inflammatory

Innate Immunity No prior “training” required • Chemical barriers • Acid in stomach, defensins in skin • Phagocytic cells • Neutrophils and macrophages • Complement and coagulation proteins • Cytokines

Toll Like Receptors • Function in both adaptive and innate immunity • Pattern recognition receptors for bacterial and viral components • Provide “second” or “danger” signal

Question #2 Which of the following patients does not need an evaluation for immunodeficiency? • A 43 year old non-smoking male who has a 5 year history of chronic sinusitis by CT scan with a new left lower lobe infiltrate • A 24 year old male hospitalized with HSV encephalitis • 5 year old girl with recurrent wheezing who has been diagnosed with pneumonia • A 43 year old female with a liver abscess that grew out Nocardiaasteroides

Question #2 Which of the following patients does not need an evaluation for immunodeficiency? • A 43 year old non-smoking male who has a 5 year history of chronic sinusitis by CT scan with a new left lower lobe infiltrate (may be common variable immunodeficiency) • A 24 year old male hospitalized with HSV encephalitis (may have TLR3 deficiency) • 5 year old girl with recurrent wheezing who had been diagnosed with pneumonia • A 43 year old female with a liver abscess that grew out Nocardiaasteroides(classic presentation of chronic granulomatous disease, a phagocyte defect)

What is an unusual infection? • Recurrent sinus infections that don’t clear with the usual treatment of antibiotics • Recurrent pneumonia (pulmonary infiltrate by chest x-ray)in the absence of tobacco use or untreated asthma • Infection with an unusual or opportunistic organism • Infection after receiving a live vaccine (BCG, varicella)

What is an unusual infection? • Viral or fungal infections of the meninges/spinal fluid • Recurrent GI infections with salmonella or parasites • Skin or organ abscesses or osteomyelitis • Oral thrush in the absence of inhaled steroids or recent antibiotics

What is considered normal?(i.e. would not trigger an immune work-up) • Recurrent UTIs (in a sexually active female or female child learning proper bathroom hygiene) • Vaginal yeast infection after antibiotics • Pneumonia in a heavy smoker who has emphysema • MRSA skin infection in a child with severe eczema • Recurrent sinus infections in an individual with untreated allergies • Ebola infection in a nurse returning from west Africa because all local facilities ran out of face shields

Primary Immunodeficiency Antibody deficiency is the most common • IgA deficiency • Common Variable Immunodeficiency • X-Linked Agammaglobulinemia +/-

IgA Deficiency • Occurs in about 1 in 700 whites in the US • Most affected individuals are asymptomatic, but some have recurrent respiratory, GI and genitourinary infections • Can be associated with celiac, RA or SLE • Reversible IgA deficiency can be caused by medications • penicillamine, sulfasalazine, valproate, hydantoin and captopril • Can progress to CVID (common variable immunodeficiency)

Common Variable Immunodeficiency • Presents as recurrent bacterial respiratory tract infections; may also have GI tract infections (Giardia) • Low IgG and often decreased IgA and IgM • Can present later in life • 50% associated with autoimmunity • Impaired antibody response to vaccines or natural infections • Defects have been found in both B cells and T cells; multiple genes have been associated with CVID +/-

X-Linked Agammaglobulinemia • Recurrent bacterial respiratory tract infections, can have GI infections and chronic enteroviral infections • Mutation in Bruton’s Tyrosine Kinase (BTK), found on the x-chromosome (only males are affected) • No circulating B cells, absent or low antibodies • Low prevalence – 1 in 100,000 to 1,000,000

Primary Immunodeficiency Cellular Immunodeficiency • Severe Combined Immunodeficiency (SCID) • Idiopathic CD4 lymphopenia (CD4+ < 300, neg for HIV) • cryptococcal, mycobacterial and other opportunistic infections • recurrent herpes virus or oral thrush • Signaling pathways are included in this grouping • IFN-gamma and IL-12 deficiency with susceptibility to mycobacterial infections

Combined T and B cell Defects • Increased susceptibility to viruses (T cells), bacterial infections (B cells and T cells), fungal infections (Candida, cryptococcus, PCP), and mycobacterial infections (T cells) • Usually diagnosed in the first year of life (if not fatal) http://www.pbs.org/wgbh/amex/bubble/

Neonatal Screening for SCID • SCID - deficiency in T & B cells +/- NK cells • Pediatric emergency – uniformly fatal in 1st 2 years of life • Avoid non-irradiated blood product transfusions • Avoid live vaccines • Low absolute lymphocytes • Absence of T-cell receptor recombination excision circles (dried blood spots) Buckley, RH. JACI 2012;129:597-604 Puck, JM. JACI 2012;129:607-16

Neonatal Screening for SCID • Barriers • Cost of developing or paying for screening • Follow-up of a positive test • Inadequate number of Immunologists in some states • Unwillingness of state Medicaid to refer out of state if needed • Cost of treating 1 baby with SCID w/serious infection > 2 million Buckley, RH. JACI 2012;129:597-604

Montana Screening for SCID • Newborn screening division at the Montana State Department of Health has been actively working on implementing this in Montana BUT failed to get it passed in 2014 for lack of funding and interest • Montana is now one of only 5 states in the US with no plans in place to start doing newborn screening • First positive by TREC assay was identified in Billings, MT. Child did not survive; had many other congenital abnormalities.

Phagocyte at work http://www.tumblr.com/tagged/phagocytosis?before=1335416339

Phagocyte Deficiency • Chronic granulomatous disease – defect in neutrophil oxidative burst • Characterized by atypical infections: • S aureus, enteric flora, P aeruginosa, S typhi, Nocardia asteroides, BCG, Aspergillus fumigatus, Candida albicans • Draining lesions in the lymph nodes of the neck or axilla, in addition to abscesses of the lung or liver requiring surgical drainage • Other phagocyte defects involve disorders of migration and chemotaxis of cells

Complement Deficiency http://www.bio.davidson.edu/courses/immunology/students/spring2006/finley/c3.html

Complement Deficiency • Absence of early complement components in the pathway results in autoimmune disease (SLE) and increased susceptibility to infection with gram positive bacteria. • C2 deficiency presents with sepsis, pneumonia, meningitis or pyogenic infections (streptococci and staphylococci) • C1 inhibitor deficiency results in hereditary angioedema • C1q deficiency manifests often as SLE • Defects in the later components of the classical cascade results in infections with Neisseria

Acquired Immunodeficiency • Acquired CD4 deficiency from HIV infection • PCP pneumonia, Toxoplasma gondii, Mycobacterium avium complex, CMV • Diabetes with poor glycemic control • Staph skin infections, Candida (oral/vaginal), Rhizopus species associated w/ ketoacidosis, Burkholderia pseudomallei (SE Asia, northern Australia) • Cancer – lymphoma or leukemia (affecting bone marrow)

Iatrogenic Immunodeficiency • Treatment for autoimmune disease • Rituximab, anti-TNF biologics, azathioprine, cyclosporine • Treatment for cancer • Cytotoxic drugs • Treatment with immunomodulators for chronic hives • Sulfasalazine can cause neutropenia • Treatment for seizures • IgA deficiency

Vitamin D Deficiency • Controversial as to what constitutes a deficiency Vit D 25OH 20 ng/ml or less? < 30ng/ml? < 40 ng/ml? • Vitamin D is used in synthesis of antimicrobial cathelicidins

Immunologic Effects of Vitamin D Mora, Nature Rev Immunol 2008 Slide borrowed from UW presentation by Carlos Carmago, MD, DrPH on October 7, 2014

Question #3 Which of the following is incorrect: • Ordering a CBC with a differential can give you the lymphocyte count • Both an SPEP and LFTs can give you an estimate of the serum globulins (IgGs primarily) • Positive Mycoplasma pneumonia antibodies confirm a patient has pneumonia

Overview • Basic Immune System Components • What constitutes an “unusual” infection? • Immunodeficiency subsets • Primary • Acquired • Iatrogenic • Screening for immunodeficiency • Treatment of immunodeficiency • Treatment of immunodeficiency

Basic Labs used to Evaluate for Immunodeficiency • CBC with differential gives absolute lymphocyte count • Is percent neutrophils > 40%? • Are eosinophils high? If greater than 400, may be allergic disease • If absolute lymphocytes are low (<0.7), may be T cell deficiency • T cells are 50-89% of the absolute lymphs, B cells are up to 20% • In LFTs, the difference between total protein and albumin is serum globulins. • If protein is < 6.2 and albumin > 4,consider ordering IgG, IgA and IgM • SPEP will flag hypogammaglobulinemia

What if IgG is low? • Normal range for IgG is generally between 700 and 1600 • If < 500 and the patient has not been on prednisone or other immune modulators, then further work-up is generally indicated • If IgG is < 150, the patient needs to be referred to an immunologist • If IgG is < 500, and the patient requires > 3 courses of antibiotics a year, assessing response to immunizations is indicated (may be selective immunodeficiency) • If IgG is between 500 and 700, and the patient has not had severe infections, consider re-checking in 6 months to a year; monitor for infections and get cultures

Vaccination response • In vivo human experiments are allowed in the case of working up selective IgG deficiency • We typically Immunize with: • Pneumovax/Prevnar 13 • H influenza B • N meningococcus (unconjugated) • Tetanus (but Medicare won’t cover antibody titers) • Assess antibody titers after 4-6 weeks “Human guinea pigs... I find that insulting!”

Cultures, cultures, cultures • Work up of an immunodeficiency can run upwards of $3,000, not including genetic testing • Getting cultures helps to direct which direction the work-up will take • Nocardia suggests phagocyte deficiency • Neisseria suggests antibody or terminal complement deficiency • Encapsulated bacterial lung infections suggest an antibody deficiency

Which Flu Vaccine should be given? • High dose Fluzone (Grade 2B recommendations in individuals > 65). • 1.4% in the high dose, and 1.9% in the regular dose group had lab confirmed influenza • US Advisory Committee on Immunization Practices has not stated a preference for Fluzone high-dose over the standard-dose inactivated influenza vaccine in older adults • Trend for increased efficacy for killed intramuscular vaccine over live attenuated intranasal vaccine (but specific data varies year to year and strain to strain) • Live intranasal vaccine (ages 2-49) contraindicated in asthmatics and immune deficient individuals

Overview • Basic Immune System Components • What constitutes an “unusual” infection? • Immunodeficiency subsets • Primary • Acquired • Iatrogenic • Screening for immunodeficiency • Treatment of immunodeficiency • Treatment of immunodeficiency

Treatment of IgG Deficiency • IgG antibody deficiencies treated with IgG infusions • IV infusions every 3-4 weeks in an infusion center • SQ infusions daily to weekly at home using a pump • Cost ranges from $50,000 to $100,000 yearly • Prophylactic antibiotics are also commonly used, particularly when a patient doesn’t meet criteria for IgG infusions • Immune deficient patients must also be monitored for • Malignancies • Decreasing lung function/bronchiectasis

Treatment of Other Deficiencies • The NIH has ongoing trials for many rare immunodeficiencies • Interferon gamma is being used to treat chronic granulomatous disease • IL-7 is being used to treat idiopathic CD4 T cell lymphopenia • Bone marrow transplant may be considered for the more severe immunodeficiencies; this is standard of care in newborns

Optimization of the Immune response • Minimize NSAIDs and acetaminophen • A fever increases efficiency of immune response (unless >101) • Exercise • Increases core body temp (see above) • Increases circulating lymphocytes • Improves response to vaccinations • Keep skin barrier intact • Consider GERD prophylaxis measures over acid suppression for benign reflux • Eat well, get enough sleep and minimize stress • Get recommended vaccinations • Gives immune system a jump start (3 days instead of 2 weeks)

Case Presentation #1 A 55 year old male smoker with a 35 pack year history of tobacco presents with his third pneumonia of the year. His last pneumonia was confirmed by a chest x-ray 3 months ago (no mass or pleural effusion). Labs done 3 months ago: protein of 7.2, albumin of 4.2. CBC shows an absolute lymphocyte count of 2.7, absolute eosinophils of 100. Additional work-up/treatment recommended: • Serum IgG, IgA and IgM • Tobacco cessation counseling • Repeat PA/LAT CXR • Spirometry

Immunodeficiency