Relevant references: see notes

Definition • Impairment of immune response due to conditions/factors extrinsic to immune system • Transient or persistent • Impaired function of cells or tissues of immune system • More frequent than primary immunodeficiency • Clinical Pearl: underlying lEI could contribute to autoimmunity, malignancy, post-treatment complications (e.g. antibody deficiency) => primary immunodeficiency can be associated with secondary immunodeficiencies as well

Most common causes

• globally: malnutrition is the most common
• otherwise there are MANY other causes:
  • drugs
  • age
  • malignancy
  • protein losing states
  • infections (ie HIV)
  • hyposplenia
  • etc...
  • structural issues (ie bronchiectasis)

regardless of the cause: all contribute to imapried immune function (ie innate vs adaptive) similar to IEI 2' immunodeficiency can also predispose to decreased tumor surveillance and immunde dysregulatrion such as autoinflammaitona dn autoimmuniulty

workup: • CBCa • Lymphocyte subset analysis • IgG/gA/IgM/|gE • Vaccine titers • Albumin, serum protein • +/-Urinalysis • Fecal a-1-antitrypsin (for protein losing enteropathies) • Liver function test • Consider HIV / HTLV testing

Clinical Pearl: Autoimmunity (e.g. autoimmune cytopenia, vasculitides), protein-losing enteropathies, excessive infection after biologics, hematologic malignancies can be due to lEl - consider genetic testing

Always consider underlying lEl... • Historical labs, imaging • Identify pre-existing hypogammaglobulinemia, lymphopenia, splenomegaly, lymphadenopathy (raises suspicion for IEl)

• Society guidelines • screening / monitoring Ig levels (e.g. in SLE, ANCA-associated vasculitis, RA, CLL, solid organ transplant - before immune suppression)

cases

Case 1: pre-teen with glomerulonephritis • Referral from Nephrology: • 11-year-old girl with MPGN type I (diagnosed age 10), on MMF • Abnormal immune tests • Treatment refractory iron deficiency anemia since age 6, chronic diarrhea, short stature/puberty delay • Recevt scope: multiple duodenal polyps • Admitted to PICU with sepsis after elective scope/polypectomy: pneumonia last year

Referral from Nephrology - Labs attached: • WBC 5.6 x 10^9/L, V Hb 88 g/L, VALC 0.8 x 10^g/L • L CD3 + 248 cells/mm3, J CD4+ 110 cells/mm3, v CD8+ 90 cells/mm3 • & 34% of CD4+ T cells RA+ (naive); J 44.2% of CD4+ T cells recent thymic emigrants • CD19+ 407 cells/mm3| • J % transitional /memory / marginal zone / switched memory B cells • & CD3-CD56+CD16+ 41 cells/mm3| • J IgG 0.69 g/L, J IgA 0.2 g/L, IgM 0.63 g/L • *Immunizations not up to date • undetectable to diphtheria, mumps • very low/nonprotective to tetanus • low to pneumococcus

• A young adolescent with: • Nephrotic syndrome • Chronic diarrhea + polyps + poor growth • On immunosuppressive medication • Yes - this is a real case (all these factors present!) • Lab evaluation • Profoundly low T cells • Profoundly low IgG/IgA • And has had serious infections

Is it primary or secondary?

History seemed concerning enough for BOTH primary and secondary So suggested: PJP prophylaxis with such low T cells and IgRT (SCIG)

specific drugs

steroids

Common lab findings in patients on steroids • Lymphopenia (especially CD4 with chronic use) • Neutrophilia • Hypogammaglobulinemia (IgG) • 12-58% adult patients on chronic/ high dose corticosteroids • Short course OCS (but not high dose ICS*) - transient drop in IgG x weeks • not associated with increased frequency or severity of infection

• High dose OCS associated with increased infection (viral/bacteria/fungal) • Due to lymphopenia > SHG • Infection proportional to duration of treatment / dose

PJP prophylaxis: if underlying immunocompromise and on high dose steroids e.g. prednisone 2 20 mg daily or equivalent, > 1 month, and for 1 month after discontinuation

B-cell depleting agents • Anti-CD20 monoclonal antibodies • Treatment of autoimmune disease, lymphoid malignancy • Hypogammaglobulinemia can develop • Associated with increased infection risk • About ½ get infection with minimum 1 dose • About 15% get low IgG • About 50% have low B cells 1 year after stopping rituximab • Chicken and egg* • autoimmunity / malignancy as feature of pre-existing lEI • Check baseline humoral immunity

Rituximab (adults) • Risk factors for post-anti-CD20 secondary hypogammaglobulinemia (SHG) • Malignant disease • Lower pretreatment IgG levels • Increased rituximab exposure • With MMF and cyclophosphamide exposure (but not with Methotrexate)

• Post-rituximab SHG associated with increased # of infections • Risk factors for infections with post-rituximab SHG • Low baseline CD4 lymphocyte counts • Post-rituximab SHG persisting > 6 months • Comorbidities (CLD, heart disease, diabetes, extraarticular RA, neutropenia requiring G-CSF) • Older age

Rituximab (adults) • B cell reconstitution occurs 6-9 months after rituximab • Varies by disease - and can take 18-24 months • Recovery of CD27+ B cells delayed beyond (?up to 10 years in some cases!) • Infections in post-rituximab SHG • Bacterial sinopulmonary (most common) • Latent HBV reactivation • PML (with case fatality rate of 90%)] • Enteroviral meningoencephalitis, CMV infection, Parvovirus B19 infection

missing slide

Conclusion: Every EBV-PTLD patient treated with rituximab must be monitored closely with regard to serum ig levels and probably have to receive IV-Ig supplementation…B-cell sub-population monitoring may probably help to understand mechanism of PH and identify high-risk patients Tell your heme/onc/BMT colleagues!

other meds

Other medications... • CAR-T (chimeric antigen receptor T cell therapy)| • can induce pure B cell aplasia in addition to hypogammaglobulinemia • SHG = most common on-target, off-tumor toxicity in CAR-T trials • Expert opinion: • screen Igs, specific vaccine Ab titers before and 3 months post CAR-T therapy • IpRT in select cases based on criteria • Anti-TNF therapies • risks for severe bacterial and mycobacterial infection (screen for Tb pre-treatment) • Eculizumab - terminal complement inhibitor • Risk for encapsulated sepsis • Immunizations, antibiotic prophylaxis

Conditions associated with secondary immunodeficiency • Hypo-albuminemic conditions • Heme malignancies (including treatment) • Infections • Non-IEl genetic causes • Congenital or acquired thymus and spleen issues • Other (SOT, burns/trauma, age extremes)

Lymphangiectasias • Dilated small intestinal lymphatic channels → lymph leakage into intestinal lumen → protein + lymphocyte loss • Variable lymphopenia, hypogammaglobulnemia • Primary or secondary • Primary: e.g. loss of function in CD55, DGAT1 • Secondary: Heart disease (e.g. ASD, repaired CHD with Fontan), infectious, neoplastic. atrogenic (e.g. chemo/rads), retroperitoneal lymphadenopathy, liver pathology (e.g cirrhosis, portal hypertension, hepatic venous outflow obstruction) • Degree of immune compromise varies by etiology • Therapy: | • low fat, high protein diet • Eculizumab in CD55 deficiency

Renal disease • Hypogammaglobulinemia in nephropathies • Urinary protein loss, reduced IgG synthesis • IgG2 disproportionately affected in nephrotic syndrome • Impact on vaccine responses • B cell targeting therapies • Chronic kidney disease • Uremia impacts innate and adaptive leukocyte function • IgG replacement • Insufficient evidence to recommend routine IgRT for SHG in nephrotic syndrome • SCIG - more stable levels, < adverse effects (e.g. fluid overload, serum osmolality) • IGRT might prevent bacterial infection in this population

Age Extremes Prematurity/infants Immature innate and adaptive immune responses Higher ALC and ANC, otherwise all immune parameters lower at birth vs. adulthood • Neonatal adaptive immunity biased toward Th2 Reduced inflammatory responses, NK cytotoxicity, conorenche • Low maternal igG in premature infants (but good response to most vaccines*) • Gut microbiome and breastfeeding

Aging/senescence • Increased infection risk and higher disease severity partly due to immune system senescence • Reduced TLR function, chemotaxis, phagocytosis, cytokine production • Altered NK subsets, cytotoxicity • Shift from naive to memory cells Thymic involution (decreased naive T cells and effector memory T subsets) B cell changes: decreased switched memory B cells, plasma cells, vaccine antibody responses

Malnutrition - increased frequency, severity of infections • Infections also result in limited food intake and absorption, and increased metabolic needs • Protein-energy malnutrition in children • Demonstrated impacts on innate and adaptive immune system • Adequate nutrition restores normal immune responses • Micronutrient deficiencies specifically: zinc selenium vit A C D E

Also genetic suyndromes OTHER than IEI ... Down syndrome (Trisomy 21) • Subset with increased infection, autoimmunity, autoinflammation, heme malignancy • Dysregulated expression of chromosome 21 genes, especially IFN-related • Some with smaller thymus, premature thymic involution • Some with hypogam, reduced naive/memory B cells due to higher B cell apoptosis • OM in childhood most common - improves over time • Infections related to: • abnormal immune response • anatomic (macroglossia, enlarged tonsils/adenoids, small ainways/hypopharynx, eustachian dysfunction), • allereic inflammation • Other: • Primary Ciliary Dyskinesia, Turner syndrome • Cystic fibrosis: | • Abnormal neutrophil, macrophage, lymphocyte and DC function reported • Hypergammaglobulinemia may be marker of lung disease severity and prognosis*

Asplenia/Hyposplenia • Surgical • E.g. after trauma, or treatment of autoimmune cytopenia or malignancy • Functional asplenia • Repeated ischemia or infarcts (e.g. sickle cell diseases) • Impact on adaptive immune response • Increased susceptibility to encapsulated organisms e.g. S. pneumoniae • Evaluation • Pitted red cell count, IgM memory B cell count • Management • Vaccinations: S. pneumoniae, N. meningitidis, H influenzae type b, Influenza* • Antibiotic prophylaxis (children <5 years at higher risk due to not vet having specific antibody iters to childhood

mgment

cure and identify the cause first then supportive care

reduce epxousre to infections IVIG or SCIG antiboitc prophuylaixs

when to start IGRT?

• First, try to remove trigger / treat cause (if possible) • Ensure all supportive care taken • Immunizations, antimicrobial prophylaxis as indicated • Consider IgRT for SHG with / without serious/recurrent infection • Follow disease/society guidelines where available (see AAAAl paper!) • In absence of specific data: • Start for IgG <1.5 g/L (without other testing) • Start for IgG <4 g/L (solid organ transplant, heme malignancy) • Consider whether may be transient*

IgRT principles (for SHG) • Typical starting doses (0.4 - 0.6 g/kg q 4 weeks) • SCIG: fewer studies (SCIG has various advantages) | • Consider ideal body weight dosing in adults • Targets: • 8 g/L with adjustment to biological trough ('infection-free') • 4-5 g/L (SOT and heme malignancy) • 7 g/L (normal IgG in healthy adults) • 10 g/L (bronchiectasis or COPD) • Stopping • pause for 3-4 months (21 day half life, take 4-5 half lives to clear)

PEARL: most biologics ARE well tolerated and most will not cause seoncdary immunodeficiency should screen for IEI or consider it as well

Summary: • Secondary immunodeficiency can derive from various medications and medical comorbidities, including protein-losing conditions, malnutrition, malignancy, genetic syndromes, age extremes, chronic infections - and may be transient or persistent • Always consider underlying IEl in patients with suspected secondary immunodeficiency (and don't forget to consider secondary causes of immunodeficiency in your lEl patients too!) • Encourage colleagues to evaluate the patient's immune system before, during and after immune modifying therapies (and do it yourself too!) • Evaluation and treatment of secondary immunodeficiency similar to primary immunodeficiency: address cause/try to cure, and when that fails - antimicrobial prophylaxis, active/immunization strategies, IgRT