Immunodeficiency PDF

Immunodeficiency Asst. Prof Dr. Norhidayah Kamarudin MBBS (IIUM), DrPath (Med. Microbiology) (UKM) At the end of this lecture, you should be able to... 1. Define & differentiate primary & secondary immunodeficiency 2. Apply a systematic approach in identification & evaluation of cases...

Immunodeficiency Asst. Prof Dr. Norhidayah Kamarudin MBBS (IIUM), DrPath (Med. Microbiology) (UKM) At the end of this lecture, you should be able to... 1. Define & differentiate primary & secondary immunodeficiency 2. Apply a systematic approach in identification & evaluation of cases suspected of PID 3. Describe common PIDs in terms of a. pathophysiology b. clinical features c. principle of investigation d. principle of management 4. Describe common causes of secondary immunodeficiency & its principle pathophysiology  Definitions Primary Secondary Immunodeficiency Immunodeficiency congenital disease acquired condition that might affect any caused by other non- aspect of the immune immunological disease response PID; It is not uncommon Epidemiology It carries a significant morbidity & mortality US data: Selective IgA deficiency (1/223- 1/1000 population) SCID 1/58 000 live births, comparable to leukemia. At least 1 in 1200 persons has been diagnosed with PID  Epidemiology cont., Situations in Malaysia: 1st case reported in 1977, in UH KL 1986-2011, 235 confirmed cases. A systematic review published in 2020 identified only 119 PID cases from 34 publications, estimating a prevalence rate of 0.37 per 100,000 population. This figure is significantly lower than global estimates, suggesting underreporting/underdiagnosis of PID in Malaysia. Limited awareness among healthcare professionals, insufficient diagnostic facilities, and the absence of a national PID registry.  PID Death Severe Combined 100% Immunodeficiency Outcome of PID in X-Linked Agammaglobulinemia 66% Malaysia before 2000 Chronic Granulomatous Disease 50% Chediak Higashi 100% Average PID death 66% Epidemiology cont., There are more than 300 different forms of PID. Components of the immune system that are frequently affected by PID: Nonspecific host immune defense system: Phagocytosis e.g. CGD, LAD Complement Specific immunity: Cell-mediated immunity: T lymphocyte Antibody-mediated immunity: B lymphocyte Combination of both Approach to a Patient Suspected of PID 1. Relevant clinical history 2. Findings on physical examination 3. Principle of investigation 4. Principle of management Clinical manifestations Onset of symptoms may appear as early as 6 months. Rate & severity of infection exceeds normal expectations. Unusually hard to cure the infection. If someone presents with ≥ 2 of these signs, they should be evaluated for possible PID by an immunologist 1. ≥ 4 new otitis within 1 year. 2. ≥ 2 serious sinusitis within 1 year. 3. ≥ 2 months on antibiotics with little effect. 4. ≥ 2 pneumonia within 1 year. 5. Failure to thrive (poor growth and weight gain). 6. Recurrent deep cutaneous or organ abscesses. 7. Persistent oral thrush or fungal skin infections. 8. Need of IV antibiotics to clear infections. 9. ≥ 2 deep-seated infections, such as septicemia. 10. A family history of PID. Approach in History Taking Risk factors e.g. poor environmental hygiene, passive smoker History of all infections Site, severity, need for antibiotics Past medical/ surgical Multiple hospital admissions due to infection history Congenital syndromes Poor response to vaccination Immunization history Adverse reaction to live viral vaccine Product of consanguineous marriage Family & social history Fhx of serious infections, unexplained sudden early infant death, diagnosis of PID and autoimmune disease Physical Examination Weight and height Growth centiles that fall below expected norms (FTT) Structural damage from infections: superficial (scars, abscesses) or deep organ involvement e.g. lung scarring/changes Paucity of lymphoid tissues e.g. tonsils & lymph nodes (XLA) Autoimmune features e.g. vitiligo, alopecia, goitre Associated congenital anomalies (e.g. DiGeorge) Other disease-specific findings Approach in Investigation Basic lab tests FBC & full blood picture Advance/ exotic lab tests Aim to detect the presence and determine the function of the different parts of the immune system. Advance Lab Tests 1. B-lymphocyte IgG, IgA, IgM, IgE level (Total and/or relevant subclasses). Ig function by measuring: isohemagglutinins level ( IgM anti-A, anti-B titres) antibody level, produced in response to immunization with unconjugated purified pneumococcal polysaccharide vaccine a 4-fold rise in antibody titre to diphtheria or tetanus toxoid after booster immunization. Pokeweed mitogen and antigen-stimulated antibody production in vitro B cell numbers by flow cytometry Advance Lab Tests cont., 2. T-lymphocyte: T cell numbers and surface phenotypes (flow cytometry) Evaluate T-cell function by its response to antigens, mitogens e.g. OKT3, phytohaemagglutinin (PHA), Concanvalin A (ConA), phorbol myristate acetate (PMA) 3. Phagocyte: Measure of oxidative metabolism e.g. DHR assay, NBT test Measure of phagocytosis e.g. candidacidal/bactericidal test 4. Complement: Measurement of specific components e.g. C3, C4 Advance Lab Tests cont., 5. Genetic studies Essential investigation for diagnosis and management Cytogenetics, X-linked gene studies, fluorescent in situ hybridization for microdeletions, protein expression studies, MHC studies, whole exome or whole genome sequencing Other tests Imaging e.g. CXR, CT scan Normal infant CXR with thymus shadow Infant CXR with absence of thymus shadow Principle of Management Early diagnosis and treatment is crucial to prevent severe complications. Supportive treatment e.g. parenteral antibiotics Hematopoietic stem cell transplantation (HSCT); improve survival & outcome (particularly for SCID). Immune replacement therapy e.g. with human immunoglobulin. Primary Humoral Immunodeficiency “inability of the humoral immune system to produce sufficient quantities of protective antibodies to properly protect the host from hazardous antigens” 1. X-linked agammaglobulinemia (XLA) 2. Common variable immunodeficiency (CVID) 3. Selective IgA deficiency 4. Hyper IgM syndrome Classification of primary antibody deficiency diseases 1. X-linked Agammaglobulinemia: Bruton Disease First described in 1952 Epidemiology: Prevalence of 1 in 10 000 Primarily affect X-linked disease  Pathogenesis: Mutation in the X chromosome affecting btk gene that codes for tyrosine kinase, an enzyme that facilitates B-lymphocyte maturation (pre-B cell signal transduction) Gene is located at Xq21.3-22. Mutations include deletions and point mutations. Causing failure of pro-B cell to differentiate into B cell (maturation stop after heavy chain gene rearrangement). No mature B cell & no light chain production. Thus, no complete Ig molecule is being produced. Resulting in the absence of all types of immunoglobulins. 1. XLA cont., Clinical manifestations: Infant Onset early in childhood, after 6 months old which coincides with the disappearance of maternal antibody. Positive FHx Failure to thrive No tonsils 1. XLA cont., Recurrent bacterial infection of lungs and ears. Including chronic pharyngitis, otitis media, bronchitis, pneumonia (may progress to bronchiectasis, pulmonary failure & death at early age), meningitis, septic arthritis Infection by bacteria typically cleared by antibody opsonization e.g. Haemophilus influenzae type B Streptococcus pneumoniae Staphylococcus aureus Salmonella, Campylobacter infections (presents with chronic diarrhea) Viruses e.g. enteroviruses Parasite e.g. Giardia lamblia 1. XLA cont., Investigation: Enumeration of lymphocytes: Absent of BTK protein Absent/ markedly low circulating B Definitive diagnosis: Genetic cell Normal pre-B cell in marrow analysis for btk gene mutation Absence of plasma cells Histological examination: Normal T-lymphocyte & NK-cell Underdeveloped/ rudimentary numbers and function germinal centre in peripheral Immunoglobulin: lymphoid tissues All immunoglobulins are absent or very low. Functional test of specific antibody production; suppressed 2. Common Variable Immunodeficiency Phenotypically heterogenous group of congenital disorders characterized by hypogammaglobulinemia of variable basis. Epidemiology: Prevalence of 1 in 25 000 to 60 000 Peak presentation at early childhood and early adulthood. 2. CVID cont., Etiology: Unknown Hypothesis suggests environmental insult (? virus infection) in a genetically susceptible individual. Likely involves interactions between genetic mutations, immunologic dysfunctions, and environmental triggers. Pathogenesis is complex & multifactorial. B cells can recognize antigens and respond with proliferation, but their ability to develop into memory B cells or mature plasma cells appears quantitatively impaired. 2. CVID cont., CVID is a diagnosis by exclusion. Other genetic diseases need to be ruled out first. Its diagnostic criteria patient > 4yo, with deficient of >1 major antibody class, & whose antibody response to vaccination is significantly depressed or absent. 2. CVID cont., Similar clinical presentation as Bruton’s except: = May manifest late in life (2nd or 3rd decade) May present with autoimmune problems (e.g. haemolytic anaemia, pernicious anaemia, organ-specific AI disease e.g. thyroid, diabetes, vitiligo, and alopecia). 2. CVID cont., Investigation: Lymphocyte count: B-lymphocyte count may be normal or lymphopenia Absent plasma cell (CD27+ B cell) Normal mature B cell morphology Immunoglobulin levels are variably low with poor/absence immunization responses Nodular lymphoid hyperplasia of bowel (polyclonal hyperplasia of Peyer’s patches) is unique to CVID. 3. Selective IgA deficiency Most common PID 1 in 400 to 800 population Unknown molecular basis. Clinical manifestations: Mostly asymptomatic Association with allergic disorders (e.g. food allergies and intolerances) and often with autoimmune disorders (e.g. SLE, rheumatoid arthritis) Infections are rarely a problem unless in the presence of other additional humoral defects.  Investigation: Undetectable IgA (including secreted IgA) Normal IgM, normal or elevated IgG Autoantibodies may be present Elevated IgE in the presence of allergic disease Normal T-lymphocyte function 4. Hyper IgM Syndrome Pathogenesis: Deficiency in CD40 ligand (CD154) on T-lymphocyte, required for B- lymphocyte immunoglobulin class switch The gene is located at Xq26-27 4. Hyper IgM Syndrome cont., Clinical manifestation 70% male X-linked but may also have AR or AD inheritance. Recurrent pyogenic infection (low level IgG for opsonization) Association with autoimmune disorders 4. Hyper IgM Syndrome cont., Investigation: Elevated IgM (and IgD) IgM level may be normal in the absence of infection Markedly reduced serum IgG, IgA & IgE level Elevated isohaemagglutinins Normal number of circulating B cells Defective CD40 ligand expression on activated T-lymphocyte Primary T cell Immunodeficiency A group of disorders are caused by defects in genes critical to the growth, maturation, and survival of T lymphocytes 1. Severe combined immunodeficiency (SCID) 2. Combined immunodeficiency with immune dysregulation & syndromic features: 2.1 DiGeorge syndrome 2.2 Wiskott Aldrich syndrome 1. Severe Combined Immunodeficiency (SCID) A constellation of genetically distinct syndromes, but all exhibiting defects in both cellular and humoral-mediated immune response. CD4+ T cell and B cell interaction. 1 in 50 000 births  X-linked (50-60% of SCID) Mutation of gene that encode common gamma chain shared by cytokine receptors for IL-2, IL-4, IL- 7, IL-9, IL-15 Prerequisite interaction responsible for stimulating survival Mostly affect CD4+ helper T cell & expansion of immature B & T cell Resulting in impaired of both precursors in marrow. cellular & antibody mediated immunity. Mutation in adenosine deaminase (20% of SCID). AR inheritance Defective purines metabolism. 1. SCID cont., ADA function in purine metabolism. Absent ADA will caused accumulation of triphosphate metabolites (adenosine & deoxyadenosine) that will inhibit DNA synthesis & toxic to lymphocytes.  Another spectrum of SCID with autosomal recessive in inheritance: Defect in another purine metabolic pathway. MHC class II deficiency. Mutation in recombinant genes responsible for effective rearrangement of lymphocyte antigen-receptor molecules. 1. SCID cont., Clinical manifestations are similar despite genetically distinct syndrome. Hallmarks of SCID include: consistent manifestation in the first year of life (4-6 month), with repeated life-threatening bacterial/ viral/ fungal infections, chronic diarrhea, and failure to thrive 1. SCID cont., Susceptible to severe recurrent infection by wide array of pathogen Bacteria e.g. pseudomonas Viruses of low pathogenicity- opportunistic infection e.g. by CMV systemic infection with attenuated viruses e.g. live viral vaccines (BCG, polio vaccine) Fungi- opportunistic infection e.g. by candida albicans (oral thrush), pneumocystis jiroveci pneumonia, systemic deep fungal infection 1. SCID cont., Investigations: T-, B-, NK- and T-cell subpopulations with absolute number lymphopenia ( acquired. Clinical manifestations: Majority is asymptomatic Symptomatic- candida infections (mucocutaneous, meningeal, bone, systemic)- unexplained, recurrent, invasive. Associated with increased risk of chronic inflammatory diseases e.g. polyarthritis, autoimmune lupus nephritis, diabetes mellitus 2. Myeloperoxidase def. cont., MPO is synthesized in neutrophils and monocytes, packaged in azurophilic granules, and released either into the phagosome or the extracellular space. MPO catalyses the conversion of H2O2 which leads to the amplification of toxicity of the ROS generated during the respiratory burst. MPO deficiency occurs due to the translational defect in the MPO gene. 2. Myeloperoxidase def. cont., Diagnosis immunocytochemical staining of neutrophils to look for MPO 3. Chédiak–Higashi syndrome AR inheritance Characterized by failure of lysosomes within the neutrophils to fuse with phagosome, resulting inability to kill of phagocytosed pathogen. 3. Chédiak–Higashi syndrome cont., Pathophysiology lies in the mutant gene encodes for cytoplasmic protein i.e. the microtubules, involve in protein transport. Clinical manifestation, similar as CGD. Investigation: Examination of neutrophil under microscope may reveal large cytoplasmic granular inclusions (abnormal lysosomes). Production of oxidative burst is normal. Normal B & T cells. Management: Supportive antibiotic therapy 4. Leukocyte Adhesion Deficiency (LAD) Results from the inability of neutrophils to migrate to the site of infection. LAD-1 is the most common: defect in β2 integrin typically presented with failure of umbilical cord separation & omphalitis Predominant presentation of bacterial infection commonly by Staph. aureus or gram negative bacteria. Forms of infection include gingivitis, periodontitis, necrotizing ulcerative skin infections 4. LAD cont., Investigation: marked granulocytosis Management: antibiotic prophylaxis, HSCT 5. Hyper-IgE Syndrome AD inheritance Pathogenesis Mutations in the DNA-binding domain of signal transducer and activator transcription (STAT3) causing defective Th17 function. Impairs production of IL-17 and IL-22 by Th17 cells IL-17 is crucial for neutrophil recruitment to infection sites. As a result, neutrophils fail to properly migrate to infected tissues, leading to chronic and recurrent bacterial infections  Clinical manifestations: Eczema Recurrent invasive bacterial infection (Staphylococci and Haemophilus) Investigations: Massive IgE elevation Variable abnormalities in neutrophil function affecting chemotaxis, phagocytosis, and microbicidal activity Secondary Immunodeficiency Acquired conditions that disrupt the development or function of an otherwise normal immune system  Secondary immunodeficiency is an acquired condition resulted by a wide variety of factors that affect the immune function such as: 1. malnutrition 2. viral infection e.g. HIV 3. iatrogenic immunosuppression e.g. post-organ transplant, chemo or radiotherapy 4. cancer metastasis or leukemias especially those involving bone marrow 5. chronic disease, debility, or stress 6. advanced age 1. Malnutrition Malnutrition may lead to: lymphocyte dysfunction alter innate mechanism of immunity Under & over nutrition, both are associated with altered immune responses 2. Immunodeficiency secondary to drug therapies Immunosuppressive therapy post organ transplant is necessary to avoid graft-versus-host disease (GvHD): suppression of cellular mediated immunity Glucocorticoid as a powerful immune modulators: affect both innate & adaptive immune function Corticosteroids cause immunosuppression mainly by sequestration of CD4+ T cells in the RES and by inhibiting the transcription of cytokines. 3. HIV Infection Direct effect of immune dysfunction: loss of CD4+ T cells due to direct killing by HIV HIV cont., Indirect effect of HIV on immune function Impair innate immunity mechanisms NK cell function dramatically altered Dysregulation of cytokines production Impair CD8+ T cell function Weakened adaptive immunity Other viral infection that primarily targets immune cells can potentially lead to immunosuppression e.g. infection by Cytomegalovirus and Epstein Barr Virus. 4. Diseases leading to reduction Ig production Disease primarily affecting the lymphocytes or plasma cells e.g. Hodgkin/ Non-Hodgkin lymphoma Chronic Lymphoblastic leukemia Multiple myeloma Waldenstrom macroglobulineamia  5. Metabolic diseases e.g. DM Pathogenesis of immunodeficiency in diabetes mellitus. AB, antibody ; AGE, advanced glycation end product; C4, complement factor 4; G6PD, glucose-6-phosphate dehydrogenase; IFN-γ, interferon-γ; Ig, immunoglobulin; IL-#, interleukin-#; LPS, lipopolysaccharide; MHC, major histocompatibility complex; PBMC, peripheral blood mononuclear cells; PMNL, polymorphonuclear leukocytes; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.  Primary factors that increase the risk of bacterial infection in a diabetic patient include disturbances in humoral innate immunity (e.g., complement and cytokines), cellular innate immunity of PMNLs (e.g., chemotaxis, adherence, phagocytosis, and bactericidal activity) and monocytes/macrophages Thank you