Primary Immunodeficiency Quiz
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Which factor most significantly contributes to the underreporting of Primary Immunodeficiency (PID) cases in Malaysia, compared to global estimates?

  • Advanced diagnostic facilities that quickly resolve immune issues.
  • Higher genetic resistance to immune disorders among the Malaysian population.
  • A national PID registry that efficiently tracks all reported cases.
  • Limited awareness among healthcare professionals about PID. (correct)

    • A child is suspected to have a Primary Immunodeficiency (PID). Which of the following represents a critical first step in a systematic approach to evaluating this case?

  • Performing genetic sequencing to identify specific mutations.
  • Immediately initiating broad-spectrum antibiotic treatment.
  • Assessing the patient's history for recurrent or severe infections. (correct)
  • Administering immunoglobulin therapy as a preventive measure.

    • How do primary and secondary immunodeficiencies differ in their origins?

  • Primary immunodeficiencies affect only B-cells, while secondary affect only T-cells.
  • Primary immunodeficiencies are congenital, while secondary immunodeficiencies are acquired. (correct)
  • Primary immunodeficiencies are acquired, while secondary immunodeficiencies are congenital.
  • Primary immunodeficiencies result from environmental factors, while secondary are genetic.

    • Before the year 2000, what was the average mortality rate for Primary Immunodeficiency (PID) cases in Malaysia?

    <p>66% (C)</p> Signup and view all the answers

    Which component of the immune system is directly affected in Chronic Granulomatous Disease (CGD), a type of Primary Immunodeficiency?

    <p>Phagocytosis (A)</p> Signup and view all the answers

    A patient with suspected primary antibody deficiency receives a pneumococcal polysaccharide vaccine. Which result would suggest an impaired B-cell function?

    <p>No significant increase in antibody levels after vaccination. (D)</p> Signup and view all the answers

    A child is suspected of having a T-lymphocyte disorder. Which of the following laboratory tests would be MOST appropriate to evaluate T-cell function?

    <p>Flow cytometry to determine T cell numbers and surface phenotypes. (A)</p> Signup and view all the answers

    A patient's lab results show recurrent infections and reduced C3 and C4 complement levels. Which of the following follow-up tests is MOST relevant to understanding the underlying cause?

    <p>Genetic studies, including whole exome sequencing. (B)</p> Signup and view all the answers

    An infant's chest X-ray reveals an absence of the thymus shadow. This finding should prompt further investigation for which condition?

    <p>Severe Combined Immunodeficiency (SCID) (A)</p> Signup and view all the answers

    Why is early diagnosis and treatment crucial in managing primary immunodeficiency disorders?

    <p>To prevent severe complications and improve overall outcomes. (B)</p> Signup and view all the answers

    Which of the following conditions is associated with defects in phagocytic cells, impacting the patient's ability to combat bacterial and fungal infections?

    <p>Chronic Granulomatous Disease (CGD) (B)</p> Signup and view all the answers

    A child presents with recurrent otitis media, sinusitis, and pneumonia. Initial investigations reveal normal lymphocyte counts but low serum IgG, IgA, and IgM levels. Which type of immune deficiency is most likely?

    <p>B-cell deficiency (D)</p> Signup and view all the answers

    A patient is suspected of having a primary immunodeficiency (PID). After taking a relevant clinical history and completing a physical examination, what is the next principle to follow in the evaluation?

    <p>Principle of investigation (D)</p> Signup and view all the answers

    A 9-month-old infant has had four episodes of otitis media in the past year, two serious sinus infections, and persistent oral thrush. According to the diagnostic criteria for primary immunodeficiency (PID), how many of these signs must be present to warrant further evaluation for possible PID?

    <p>At least two signs (B)</p> Signup and view all the answers

    When taking a patient's history to evaluate for possible primary immunodeficiency, which of the following is the MOST relevant information to gather regarding their infection history?

    <p>Site, severity, and need for antibiotics for all infections (A)</p> Signup and view all the answers

    During a physical examination for suspected primary immunodeficiency, what finding would MOST strongly suggest a B-cell related immune defect?

    <p>Paucity of lymphoid tissues (C)</p> Signup and view all the answers

    Which of the following statements regarding the etiology of Common Variable Immunodeficiency (CVID) is most accurate?

    <p>CVID likely arises from a complex interplay of genetic predisposition, immune system dysfunction, and environmental triggers. (A)</p> Signup and view all the answers

    A 6-year-old patient presents with recurrent respiratory infections and a history of poor response to vaccinations. Initial immunoglobulin testing reveals low levels of IgG and IgA, but normal levels of IgM. To differentiate CVID from other possible immunodeficiencies, which additional criteria must be met for a CVID diagnosis?

    <p>Other genetic causes of immunodeficiency must be excluded. (C)</p> Signup and view all the answers

    What is the purpose of measuring IgG, IgA, IgM, and IgE levels as an advanced lab test in the investigation of primary immunodeficiency?

    <p>To detect the presence and quantify the levels of different immunoglobulin isotypes produced by B-lymphocytes (C)</p> Signup and view all the answers

    How does the clinical presentation of CVID typically differ from that of Bruton's agammaglobulinemia?

    <p>CVID can manifest later in life and may involve autoimmune complications, whereas Bruton's agammaglobulinemia typically presents earlier in life with a greater susceptibility to infections. (D)</p> Signup and view all the answers

    A family brings their child in due to suspected PID. What aspect in the family and social history would be MOST relevant in determining if it is PID?

    <p>Family history of serious infections, unexplained sudden early infant death, diagnosis of PID and autoimmune disease (C)</p> Signup and view all the answers

    A patient is suspected of having CVID. Which of the following investigation results would be most indicative of CVID?

    <p>Low immunoglobulin levels, poor immunization responses, with absent plasma cells (CD27+ B cells). (B)</p> Signup and view all the answers

    A 30-year-old patient is diagnosed with Selective IgA Deficiency. Besides monitoring for infections, what other conditions should this patient be regularly screened for due to the association with IgA deficiency?

    <p>Allergic disorders and autoimmune diseases. (B)</p> Signup and view all the answers

    A male patient presents with recurrent pyogenic infections and is suspected of having Hyper IgM Syndrome. Genetic testing reveals a mutation on the X chromosome. Which of the following is the MOST likely underlying pathogenesis?

    <p>Deficiency in CD40 ligand (CD154) on T-lymphocytes, impairing B-lymphocyte immunoglobulin class switch. (A)</p> Signup and view all the answers

    A newborn is diagnosed with Severe Combined Immunodeficiency (SCID). Further investigation reveals a defect leading to impaired purine metabolism. Which specific enzyme is MOST likely deficient in this patient?

    <p>Adenosine Deaminase (ADA) (A)</p> Signup and view all the answers

    A child is suspected of having Hyper IgM Syndrome. Lab results show elevated IgM levels but normal circulating B cell numbers. What other lab findings would support the diagnosis?

    <p>Markedly reduced serum levels of IgG, IgA, and IgE (A)</p> Signup and view all the answers

    Which of the following BEST describes the PRIMARY immunological defect in X-linked Severe Combined Immunodeficiency (SCID)?

    <p>Impaired development and function of T cells due to a mutation affecting cytokine receptor signaling. (D)</p> Signup and view all the answers

    Why does a defect in the common gamma chain shared by cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15) primarily affect CD4+ helper T cells in X-linked SCID?

    <p>The signaling through these cytokines is essential for the survival and expansion of immature T cells, particularly CD4+ helper T cells. (C)</p> Signup and view all the answers

    In Severe Combined Immunodeficiency (SCID) caused by Adenosine Deaminase (ADA) deficiency, which of the following mechanisms directly contributes to lymphocyte toxicity?

    <p>Accumulation of triphosphate metabolites, inhibiting DNA synthesis. (A)</p> Signup and view all the answers

    Why are individuals with Severe Combined Immunodeficiency (SCID) particularly susceptible to infections from attenuated live viral vaccines, such as the BCG or polio vaccine?

    <p>The impaired immune system in SCID cannot control even weakened forms of the virus, leading to systemic infection. (D)</p> Signup and view all the answers

    A clinician suspects a patient has Severe Combined Immunodeficiency (SCID). Which initial laboratory finding would strongly support this diagnosis?

    <p>Lymphopenia with decreased T-cell subpopulations. (B)</p> Signup and view all the answers

    Which of the following is a common clinical manifestation observed in infants within the first year of life who have Severe Combined Immunodeficiency (SCID)?

    <p>Repeated, life-threatening bacterial, viral, or fungal infections. (B)</p> Signup and view all the answers

    In Myeloperoxidase (MPO) deficiency, what is the primary consequence of impaired MPO function on neutrophil activity?

    <p>Impaired amplification of the toxicity of reactive oxygen species during the respiratory burst. (D)</p> Signup and view all the answers

    A patient is diagnosed with Myeloperoxidase (MPO) deficiency but remains largely asymptomatic. What is the most likely explanation for the lack of severe infections in this individual?

    <p>Redundant compensatory mechanisms exist within the immune system to counteract the MPO deficiency. (A)</p> Signup and view all the answers

    What cellular process is primarily disrupted in Chédiak–Higashi syndrome, leading to impaired pathogen clearance?

    <p>Failure of lysosomes to fuse with phagosomes in neutrophils. (C)</p> Signup and view all the answers

    The underlying genetic defect in Chédiak–Higashi syndrome affects a cytoplasmic protein that is essential for what process?

    <p>Lysosomal trafficking and fusion. (B)</p> Signup and view all the answers

    Flashcards

    Primary Immunodeficiency

    A congenital disease affecting any aspect of the immune response.

    Secondary Immunodeficiency

    An acquired condition caused by non-immunological diseases.

    Common causes of Secondary Immunodeficiency

    Includes diseases like HIV, malnutrition, and cancer.

    Severe Combined Immunodeficiency (SCID)

    A PID with high morbidity; affects T and B cell functions.

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    Epidemiology of PID

    PID affects 1 in 1200 people; underreported in some regions.

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    PID signs

    Indicators for potential Primary Immunodeficiency Disease that need evaluation.

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    Clinical manifestations

    Early symptoms of PID may appear as early as 6 months.

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    Recurrent infections

    Signs such as multiple sinusitis or otitis in a year indicating PID.

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    Failure to thrive

    Poor growth and weight gain indicating possible PID.

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    History taking

    Gathering relevant medical and social history for PID evaluation.

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    Physical examination

    Assessments including weight and structural damage from infections.

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    Basic lab tests

    Initial tests like FBC to evaluate the immune system.

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    Advanced lab tests

    Tests aimed at assessing function of different immune system components.

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    Isohemagglutinins

    IgM antibodies that react to A and B blood group antigens.

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    T-cell function evaluation

    Assessed by response to antigens using mitogens like PHA.

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    Phagocytic function test

    Measurement of phagocytosis and oxidative metabolism in phagocytes.

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    Complement components

    Measured components in the immune system, e.g. C3, C4.

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    Primary Humoral Immunodeficiency

    Inability to produce enough antibodies for protection against antigens.

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    Hyper IgM Syndrome

    A genetic disorder caused by CD40 ligand deficiency affecting Immunoglobulin class switching.

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    Recurrent Infections in Hyper IgM

    Patients experience recurrent pyogenic infections due to low IgG levels for opsonization.

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    Clinical Findings in Hyper IgM

    Clinical features include elevated IgM, reduced IgG, IgA, and IgE, with normal B cell counts.

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    Role of ADA in SCID

    Adenosine deaminase is critical for purine metabolism; mutations lead to SCID in 20% cases.

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    ADA Deficiency

    Absence of adenosine deaminase leads to toxic metabolite accumulation, inhibiting DNA synthesis.

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    SCID Hallmarks

    Signs include life-threatening infections in the first year, chronic diarrhea, and failure to thrive.

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    Infections in SCID

    Patients are susceptible to bacterial, viral, and fungal infections due to immune deficiency.

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    MPO Deficiency

    Myeloperoxidase deficiency impairs neutrophil function, leading to recurrent infections.

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    MPO Diagnosis

    Diagnosis involves immunocytochemical staining of neutrophils to detect MPO.

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    Chédiak–Higashi Syndrome

    A genetic disorder resulting in ineffective lysosomal fusion in neutrophils, impairing pathogen killing.

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    Lymphopenia

    Condition characterized by a low number of lymphocytes, often seen in SCID.

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    Chronic Inflammatory Diseases in SCID

    Patients may experience increased risk of disorders like autoimmune diseases due to immune dysregulation.

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    Common Variable Immunodeficiency (CVID)

    A primary immunodeficiency characterized by low antibody response and frequent infections.

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    CVID Diagnosis Criteria

    Diagnosis requires patient >4 years old with low antibody levels and poor vaccination response.

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    CVID Clinical Presentation

    CVID may show symptoms late in life and can include autoimmune disorders.

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    Selective IgA Deficiency

    The most common primary immunodeficiency with low IgA levels and sometimes allergic associations.

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    Tests for Selective IgA Deficiency

    Diagnosis involves checking undetectable IgA levels with normal IgM and IgG.

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    Study Notes

    Immunodeficiency Overview

    • Immunodeficiency is a condition where the immune system's ability to fight off infection is compromised.
    • It can be categorized as primary (inherited) or secondary (acquired).

    Primary Immunodeficiency Definitions

    • Primary Immunodeficiency (PID): A congenital disease inherited from parents that affects any aspect of the immune system response.

    Secondary Immunodeficiency Definitions

    • Secondary Immunodeficiency: An acquired condition caused by other non-immunological diseases.

    PID Epidemiology

    • PID is not uncommon, but less prevalent in Malaysia than other countries.
    • It significantly impacts health, contributing to high morbidity and mortality.
    • US data: Selective IgA deficiency (1/223-1/1000 population), Severe Combined Immunodeficiency (SCID) 1/58,000 live births (comparable to leukemia), at least 1 in 1200 persons diagnosed with PID.
    • Malaysian data (limited awareness, insufficient diagnostic facilities, absence of national PID registry): 119 PID cases identified in a 2020 review of 34 publications, estimating a prevalence rate of 0.37 per 100,000 population. Significant underreporting/underdiagnosis of PID.

    PID Outcomes Before 2000 in Malaysia

    • Average PID death rate before 2000: 66%
    • Specific PID outcomes (Severe Combined Immunodeficiency, X-Linked Agammaglobulinemia, Chronic Granulomatous Disease, Chediak Higashi): variable mortality rates ranging from 50% to 100%, depending on the specific disease.

    Components of the Immune System Frequently Affected by PID

    • Nonspecific host immune defense system: Phagocytosis (e.g., CGD, LAD), Complement.
    • Specific immunity: Cell-mediated immunity (T lymphocytes), Antibody-mediated immunity (B lymphocytes), Combination of both.

    Approach to a Patient Suspected of PID

    • Relevant clinical history
    • Physical examination findings
    • Investigation principles
    • Management principles

    Clinical Manifestations of PID

    • Onset of symptoms can begin as early as 6 months.
    • Rate and severity of infections often exceed expected norms.
    • Infections are challenging to cure.
    • Ten warning signs include (among others): four or more new ear infections within a year, two or more pneumonias within a year, and persistent thrush or fungal skin infections.

    Approach to History Taking

    • History of all infections
    • Past medical/surgical history
    • Immunization history
    • Family and social history (risk factors like poor environmental hygiene, passive smoking, multiple hospitalizations, consanguineous marriage, family history of serious infections, unexplained early infant death, diagnosis of PID or autoimmune disease)

    Physical Examination

    • Weight and height are often below expected norms.
    • Signs of structural damage from infections (e.g., scars, abscesses).
    • Assessment of lymphoid tissue (e.g., tonsils, lymph nodes).
    • Examination for autoimmune features (e.g., vitiligo, alopecia, goitre).
    • Assessment of associated congenital anomalies (e.g., DiGeorge syndrome).
    • Examination for other disease-specific findings.

    Investigation Principles

    • Basic lab tests (full blood count) → expensive, rare exotic tests.
    • Advanced/exotic lab tests aim to identify presence & function of different immune system components.

    Advanced Lab Analysis

    • B-lymphocytes: IgG, IgA, IgM, IgE level or relevant subclasses; Isohemagglutinins (IgM anti-A, anti-B titres); Antibody production response; B cell numbers using flow cytometry.
    • T-lymphocytes: T-cell numbers & surface phenotypes (flow cytometry); response to antigens/mitogens.
    • Phagocytes: Oxidative metabolism (e.g., DHR assay, NBT test,) & phagocytosis (e.g., candidacidal/bactericidal test).
    • Complement: Measurement of specific components (e.g., C3, C4).
    • Genetic studies: Cytogenetics, X-linked gene studies, FISH, protein expression, MHC studies, whole/exome genome sequencing.
    • Imaging: Chest X-ray (CXR), CT scan.

    Summary of Investigation Approach

    • Take history (number, type, course of infection, family history).
    • Perform general screening for immunity (CBC, differential, platelets, antibody levels).
    • Conduct physical exam (growth and development, abnormalities, organ/tissue presence).
    • Based on findings in steps 1-2, perform disease-specific testing of immune system.

    Principle of Management

    • Early diagnosis & treatment to prevent severe complications.
    • Supportive care (e.g., parenteral antibiotics).
    • Hematopoietic stem cell transplantation (HSCT) improves survival and outcome (particularly in SCID).
    • Immunoglobulin replacement therapy (e.g., human immunoglobulin).

    Primary Humoral Immunodeficiency

    • X-linked agammaglobulinemia (XLA)
    • Common variable immunodeficiency (CVID)
    • Selective IgA deficiency
    • Hyper IgM syndrome

    1. X-linked agammaglobulinemia (Bruton's Disease)

    • First described in 1952
    • Epidemiology: Prevalence of 1 in 10,000
    • X-linked disease, Primarily affects males.
    • Pathogenesis: Mutation in the BTK gene (tyrosine kinase) affects B-cell maturation. Without BTK, B-cell maturation stops after heavy chain gene rearrangement
    • Clinical Manifestations: Recurrent bacterial infections. Infants often present with infections after disappearing maternal antibodies have decreased. In childhood, infections often start with recurrent bacteria infections in the lungs and ears
    • Investigation: Absent BTK protein; genetic analysis; histological examination, showing underdeveloped/rudimentary germinal centers in lymph nodes; Markedly low circulating B cells
    • Management: Prophylactic antibiotics, and immunoglobulin replacement.

    2. Common Variable Immunodeficiency (CVID)

    • Heterogenous group of disorders.
    • Epidemiology: Prevalence of 1 in 25,000-60,000, often arises in later childhood to early adulthood.
    • Etiology: Unknown, but possible environmental insults (viral infections) in genetically predisposed individuals.
    • Pathogenesis: Complex multi-factorial; Immune system's ability to produce memory cells, and plasma cells may be impaired.
    • Clinical manifestations: Recurrent bacterial infections, possible association with chronic inflammatory diseases, autoimmune disorders (e.g., haemolytic or pernicious anemia, thyroid disease, vitiligo).
    • Investigation: Immunoglobulin levels are variably low; Immunocytochemical testing; absence of mature B cells; often lymphopenia.
    • Management: Supportive care (e.g. antibiotics) and immune replacement therapy.

    3. Selective IgA Deficiency

    • Most common PID in population.
    • Etiology: Unknown.
    • Clinical Manifestations: Mostly asymptomatic. Often more likely to show allergies, and autoimmune disorders.
    • Investigation: Undetectable IgA; Normal IgM, IgG, and IgE; Normal T-lymphocyte function
    • Management: Supportive care (antibiotics). Typically no specific treatment needed unless infections occur frequently or are severe.

    4. Hyper-IgM Syndrome

    • AD inheritance.
    • Pathogenesis: Deficiency in CD40 ligand (CD154) on T lymphocytes impairs B-cell class switching, resulting in high levels of IgM and lower IgG, IgA & IgE production .
    • Clinical Manifestations: Recurrent infections (pyogenic).
    • Investigations: Elevated IgM and IgD; low IgG, IgA, and IgE; Normal B-cell numbers; Defective CD40 ligand expression.
    • Management: Supportive care, sometimes immunoglobulin replacement.

    Primary T-cell Immunodeficiencies

    • Severe Combined Immunodeficiency (SCID): Group of genetic syndromes; defects in both cellular and humoral immunity; CD4+ T cells and B cells fail to interact. High risk of infections, so newborn screening is high
    • Combined Immunodeficiency with immune dysregulation & syndromic features: DiGeorge syndrome and Wiscott Aldrich syndrome

    1. Severe Combined Immunodeficiency (SCID)

    • Genetic defects affect cellular and humoral immunity.
    • Clinical Manifestations: consistent manifestation in the first year of life, with repeated life-threatening bacterial/viral/fungal infections, chronic diarrhea, and failure to thrive.
    • Investigations: Absolute numbers of T, B, NK cells; Thymus hypoplasia /atrophy. Deficiencies in T/B cell response to mitogens. Genetic studies
    • Management: Protective isolation, prophylactic antibiotics; HSCT; Gene therapy.

    2.1 DiGeorge Syndrome

    • Congenital defect in the 3rd & 4th pharyngeal pouches and thymus development.
    • Clinical Manifestations: Deficient T cell maturation; vulnerable to fungal, viral and intracellular bacterial infections; parathyroid dysfunction, associated cardiac outflow tract defects; cleft palate.
    • Investigations: Absent thymic shadow on x-ray; low T-cell numbers in peripheral blood; associated abnormalities.
    • Management: Spontaneous resolution possible for some conditions. Otherwise, thymus transplantation.

    2.2. Wiskott-Aldrich Syndrome (WAS)

    • X-linked recessive mutation of gene encoding WASP protein. Defect in cytoskeletal function; affects T-cell receptor-mediated responses and immune synapse formation.
    • Clinical Manifestations: Thrombocytopenia, eczema; recurrent bacterial infections, as the T cells are depleted.
    • Investigations: Diagnostic workup may include blood testing of lymphocytes/platelets, genetic testing.
    • Management: Potentially supportive antibiotic therapy. Early bone marrow transplantation might improve prognosis.

    Complement Component Deficiencies

    • Defects in complement proteins can impair immune responses.

    Genetic Defects in Phagocytes

    • Chronic Granulomatous Disease (CGD): Defect in specific NADPH enzyme, which impairs formation of reactive oxygen species, hence inability to kill microbial pathogens.
    • Myeloperoxidase Deficiency: Deficiency in MPO enzyme, impairs killing of pathogens.
    • Chediak-Higashi Syndrome: Defect in lysosomal fusion with phagosomes, leads to inability of neutrophils to kill pathogens.
    • Leukocyte Adhesion Deficiency (LAD): Defective adhesion molecules affecting neutrophil migration; increased risk of bacterial infections.
    • Hyper-IgE Syndrome (Job's Syndrome): Resulting in defective Th17 cell function, leading to impaired neutrophil production and reduced immune response.

    Secondary Immunodeficiencies

    • Acquired conditions that affect immune system development or function.
    • Common causes include malnutrition, viral infections (HIV), Iatrogenic suppression (e.g., post-organ transplant, chemotherapy, radiotherapy), cancers (metastasis or leukemias), chronic diseases/debilities/stress, advanced age.

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    Immunodeficiency PDF

    Description

    Test your knowledge on Primary Immunodeficiencies (PID) with this quiz. It covers key concepts such as differences between primary and secondary immunodeficiencies, the evaluation of suspected cases, and immunity components affected by conditions like Chronic Granulomatous Disease. Perfect for students and healthcare professionals wanting to deepen their understanding of PID.

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