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FAILURE OF HUMAN DEFENSE MECHANISMS FAILURE OF HUMAN DEFENSE MECHANISMS * Mechanisms of Failure * Evasion and subversion of the immune system by pathogens * Immunodeficiencies * Inherited (Primary) * Acquired (Secondary) * * * * Malnutrition Drugs Radiation Pathogens MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS * Genetic variation (antigenic differences) * Numerous different surface antigens (serotypes / serovars) without modification * Streptococcus pneumoniae * 90 serotypes (capsular polysaccharides) * Salmonella species * 2,500 serotypes (cell wall polysaccharides) * Rhinoviruses * 100 serotypes (capsid proteins) * Poliovirus * 3 serotypes (capsid proteins) MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS * Genetic variation (antigenic differences) * Few different surface antigens with frequent modification * Influenza viruses * Classification into “types” on nucleoprotein * A, B and C * Classification of Influenza A virus into “subtypes * Hemagglutinin (HA or H) * Avian (16) and Human (3) * Neuramindase (NA or N) * Avian (9) and Human (2) * Influenza A subtypes (H3N2, H1N1, H5N1) MECHANISMS OF GENETIC CHANGE IN INFLUENZA A VIRUS * Antigenic Drift * Point mutations in HA and NA genes * No proofreading of replication * Minor antigenic change resulting in new “strains” * Antigenic Shift * Re-assortment of gene segments from avian and human viruses in same host (swine or humans) * Major antigenic change resulting in new “subtype” of Influenza A virus MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS * Establishment of a dormant state (latency) with reactivation * Blocking of antigen processing and presentation * * * * * * MHC I degradation Interference with proteasome Interference with TAP Interference with Tapasin Retention of MHC 1 in ER Interference with NKG2A receptor * Inhibition of humoral immunity MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS * Characteristic of the Herpesviruses * * * * * * * * Herpes simplex virus, type 1 (HSV-1) Herpes simplex virus, type 2 (HSV-2) Varicella-Zoster virus (VZV) Epstein-Barr virus (EBV) Cytomegalovirus (CMV) Human herpesvirus 6 (HHV-6) Human herpesvirus 7 (HHV-7) Human herpesvirus 8 (HHV-8) HUMAN HERPES VIRUS 8 (HHV-8) * One of seven oncogenic viruses * History of stealing human genes * IL-6, BCL-2, cyclin D * Etiologic agent * Kaposi’s sarcoma * Multicentric Castleman’s Disease * Non-malignant tumor in lymph nodes * Hyperproliferation of B cells HUMAN HERPES VIRUS 8 (HHV-8) * Target cell for latency * B lymphocyte * Mechanism of latency (genes and proteins) * Cyclin D * LANA (latency associated nuclear antigen) * K 13 * Blocks Fas apotosis pathway * Target cell for Kaposi’s sarcoma * Spindle cell MECHANISMS OF SUBVERSION OF THE IMMUNE SYSTEM * Production of exotoxins (superantigens) * Staphylococcus aureus * Streptococcus pyogenes * Staphylococcus aureus superantigens * Toxic shock syndrome toxin-1 (TSST-1) * 75% of cases (99% M and 40% NM) * Staphylococcal enterotoxin B (SEB) * 20% of cases * Staphylococcal enterotoxin C (SEC) MECHANISMS OF SUBVERSION OF THE IMMUNE SYSTEM * Streptococcus pyogenes superantigens * Streptococcus pyrogenic exotoxins A, B and C * Exotoxins produced primarily from M types * 1 and 3 * Mechanism of action * Activation of 5 to 30% of T cells * Cytokine storm TOXIC SHOCK SYNDROME (TSS) * Staphylococcal TSS * First reported in 1978 followed by outbreak in 1980 * Clinical manifestations (acute onset) * Fever (>102 F), chills, headache * Hypotension (<90 mmHg) * Diffuse macular erythroderma rash * Myalgias * Nausea, vomiting and diarrhea * Cutaneous desquamation (palms and soles) IMMUNODEFICIENCY DISEASES * A group of diseases where one or more components of the immune system are either absent or defective * Classification * Primary (Inherited) * Gene defects may be autosomal or X-linked * Secondary (Acquired) * Malnutrition, diseases, drugs, radiation, microorganisms COMPONENTS OF THE IMMUNE SYSTEM AND CLINICAL PRESENTATION IN IMMUNODEFICIENCY DISEASES * Humoral * Persons with history of recurrent infections with encapsulated bacteria * Streptococcus pneumoniae * Haemophilus influenzae * Cellular (Cell mediated) * Persons with history of recurrent infections with opportunistic pathogens * Pneumocystis jiroveci (carinii) EVALUATION OF PATIENTS WITH IMMUNODEFICIENCY DISEASES * Humoral * Measure antibody levels by nephelometry * IgM * IgG + subclasses * IgA + subclasses * Measure absolute number and percent of B cells by flow cytometry * Cellular * Measure absolute numbers and percentages of T lymphocytes by flow cytometry PRIMARY IMMUNODEFICIENCY DISEASES * WHO currently recognizes 100 primary immunodeficiency diseases * < 20 account for >90% of all cases * General Classification * * * * * * Primarily humoral deficiency Primarily cellular deficiency Combined humoral and cellular deficiency Phagocyte dysfunction or deficiency Complement deficiency MHC deficiency PRIMARY IMMUNODEFICIENCY DISEASES * Prevalence of primary immunodeficiency diseases * * * * * * B cell T cell B and T cells Phagocytes Complement NK (50 to 60%) (5 to 10%) (20%) (10 to 15%) (2%) (< 0.1%) PRIMARY IMMUNODEFICIENCY DISEASES * Most common primary immunodeficiency diseases * B cell * T cell * * * * B and T cells Phagocytes Complement NK Selective IgA deficiency DiGeorge syndrome ZAP-70 deficiency SCID Chronic granulomatous disease Immune complex disease Viral infections and tumors PRIMARY IMMUNODEFICIENCY DISEASES * Gene defects * Autosomal recessive or dominant * X-linked * Examples * * * * CVID (autosomal dominant) Selective IgA (autosomal dominant) Hyper-IgM (autosomal recessive or X-linked) Classic complement (autosomal recessive) * First PID described in 1952 * Bruton’s X-linked agammaglobulinemia CASE STUDY – 13 YEAR OLD MALE * Bone marrow transplantation (BMT) for SCID * BM from sister was unmatched * 3 months later developed * * * * Fever Nausea, vomiting and diarrhea Abdominal pain Intestinal bleeding * Autopsy revealed * Hundreds of intraabdominal malignant tumors CASE STUDY – DAVID P. VETTER * Parents – David J and Carol Ann * Children * Katherine (1968) * David J III (1970) * Died of SCID at 7 months * Advised of risk of another male child * David P born on September 21, 1971 * Unmatched BMT on 12/21/83 * Died of SCID on 2/22/84 SELECTIVE IgA DEFICIENCY * Most common and mildest of PI * Prevalence * 1 in 700 caucasians * 1 in 18,000 Japanese * Majority of patients are asymptomatic * Clinical presentation * Recurrent sinopulmonary and GI disease, allergy, autoimmunity SELECTIVE IgA DEFICIENCY * Incidence of allergy and asthma is increased * Food allergy * Asthma may be more severe * Allergic rhinitis * Incidence of autoimmune disease is increased * Rheumatoid arthritis (RA) * Systemic lupus erythematosus (SLE) * Mechanism is unclear * 30% of patients have Anti-IgA (IgG > IgM > IgE) SELECTIVE IgA DEFICIENCY * IgA deficiency significant risk factor for * Anaphylactic transfusion reactions * Mechanism is unclear * Classic anaphylaxis involves IgE * Anti-IgA, IgG most prevalent * Definition * Deficiency (< 7 mg/dL) * Severe deficiency (<0.05 mg/dL) SELECTIVE IgG DEFICIENCY * Selective IgG subclass deficiency * IgG2 in children * IgG3 in adults * Combined deficiency relatively common * IgG2 with IgA * IgG1 and IgG3 * IgG2 and IgG4 * Clinical presentation * Recurrent upper and lower respiratory tract infections SELECTIVE IgG DEFICIENCY – CASE STUDY * 9 year old male presented to family physician by his mother for evaluation of short stature and recurrent infections * Past medical history * Recurrent URI and LRI with * Streptococcus pneumoniae, Haemophilus influenzae, Influenza virus, Respiratory Syncytial Virus, Parainfluenza virus * 2 to 3 each year since age 1 * Recurrent diarrhea since age 4 SELECTIVE IgG DEFICIENCY – CASE STUDY * Laboratory results for total serum antibodies * IgG of 6.0 gm/L * IgA of 0.9 gm/L * IgM of 0.6 gm/L (5.4 to 16.1 gm/L) (0.7 to 2.5 gm/L) (0.5 to 1.8 gm/L) * Laboratory results for IgG subclasses * * * * IgG1 of 4.6 gm/L IgG2 of 0.1 gm/L IgG3 of 0.5 gm/L IgG4 of 0.2 gm/L (3.6 to 7.3 gm/L) (1.4 to 4.5 gm/L) (0.3 to 1.1 gm/L) (0.1 to 1.0 gm/L) CORRECTION OF GENETIC DEFECTS OF IMMUNE SYSTEM * Many immunodeficiencies affect hematopoietic cells * Correction of deficiency by transplantation of * Bone marrow (hematopoietic stem cells) * Success depends on degree of HLA matching between donor and recipient * Major complication graft-versus-host disease (GVHD) * Somatic gene therapy * Functional copy of defective gene inserted into patients stem cells SECONDARY (ACQUIRED) IMMUNODEFICIENCY DISEASES * Malnutrition * Diseases * Diabetes, nephrotic syndrome, protein-losing enteropathy * Drugs * Corticosteroids * Hydrocortisone, methylprednisolone, prednisone * Immunosuppressants * Azathioprine, tacrolimus, cyclosporine A ACQUIRED IMMUNODEFICIENCY DISEASES * Radiation * Microorganisms * Human T-cell lymphotropic virus, type I (HTLV-I) * Mycobacterium leprae * Lepromatous leprosy * Cytomegalovirus (CMV) * Epstein-Barr virus (EBV) * Human immunodeficiency virus (HIV) CASE STUDY – 20 YEAR OLD MALE * Presented to ER of Southeast Regional Medical Center in Lumberton, NC * Headache, fever, chills, AMS and nuchal rigidity * Blood cultures collected, but lumbar puncture was unsuccessful * Treated with single 2 gram dose of ceftriaxone * Transferred to New Hanover Regional Medical Center in Wilmington, NC CASE STUDY (20 M) – PHYSICAL EXAMINATION * VITAL SIGNS * Temperature 100 F, PR 92, RR 20, BP 120/60 * HEENT AND NECK * Pupils equal, round and light reactive * Nuchal rigidity is positive * LYMPH NODES * No lymphadenopathy * ABDOMEN * Soft. No distention, tenderness, organomegaly * EXTREMITIES * Bilateral upper and lower clubbing * NEUROLOGIC * Babinski is negative and Kernig is positive CASE STUDY – 20 YEAR OLD MALE * Past medical history * Recurrent infections (age 10) * Sinusitis * Pneumococcal pneumonia and bacteremia * Specimens collected for culture at NHRMC * Blood, CSF and ear drainage * Treatment at NHRMC * Ceftriaxone (2 grams IV q12) and vancomycin (1 gram IV q12) CASE STUDY (20 M) – COMPREHENSIVE METABOLIC PANEL (CMP) * * * * * * * * * * * * * Glucose BUN Creatinine Sodium Potassium Chloride Calcium Total Protein Albumin Bilirubin (T) AST ALT Alk Phos Patient 172 7 0.7 139 3.8 106 8.3 4.8 2.6 0.6 7 22 63 Reference 72 - 112 mg/dL 7 - 18 mg/dL 0.5 - 1.2 mg/dL 136 - 146 mmol/L 3.7 - 5.2 mmol/L 98 - 108 mmol/L 8.5 - 10.5 mg/dL 6.1 - 8.0 mg/dL 3.5 - 4.8 g/dL 0.0 - 1.0 mg/dL 15 - 37 U/L 19 - 55 U/L 50 - 136 U/L CASE STUDY (20 M) – CBC WITH DIFF * * * * * * * * * * WBC RBC Platelets HGB HCT Neutrophils Lymphocytes Monocytes Eosinophils Basophils Patient 19.8 4.2 278 11.5 33.6 85 7 7 0 0 Reference 4.8 - 10.8 K/uL 4.9 - 6.1 M/uL 145 - 400 K/uL 14.0 - 18.0 g/dL 40 - 52 % 40 - 74 % 15 - 47 % 0 - 12 % 0-6 % 0-2 % CASE STUDY (20 M) – URINE DRUG SCREEN * * * * * * * * * PCP Benzodiazepine Cocaine Amphetamine THC Opiates Barbiturates Methadone Tricyclic Antidepressants Negative Negative Negative Negative Negative Negative Negative Negative Negative CASE STUDY (20 M) – COAGGULATION/HEMATOLOGY * PT * INR * PTT * Fibrinogen * Haptoglobin * Sed rate Patient 16.6 1.93 42.8 711 425 60 Reference 10.7 - 13.5 seconds 0.86 - 1.34 seconds 25 - 38 seconds 160 - 440 43 - 212 0 - 15 mg/dL mg/dL mm/hr CASE STUDY (20 M) – CEREBROSPINAL FLUID * * * * * * * * * Glucose Protein Lactic acid WBC RBC Neutrophils Lymphocytes Monocytes VDRL 0 314 17.6 568 373 73 11 16 Negative 40 - 70 15 - 45 < 2.8 mg/dL mg/dL mmol/L uL uL % % % Negative CASE STUDY (20 M) – MICROBIAL ANTIGENS (CSF) * * * * * * Haemophulus influenzae, type B Streptococcus pneumoniae Streptococcus agalactiae (GBS) Neisseria meningitidis (C, W135) Neisseria meningitidis (A, Y) Neisseria meningitidis (B)/ E.coli * Cryptococcus neoformans Negative Negative Negative Negative Negative Negative Negative CASE STUDY (20 M) – CULTURE AND SMEAR (CSF) * Routine * 2 to 6 WBC/HPF * No organisms seen on gram stained smear * Acid-fast bacilli * No acid fast bacilli (AFB) seen on fluorochrome stained smear * Fungus * No fungal elements seen on PAS stained smear CASE STUDY (20 M) – CBC WITH DIFF (DAY 2) Patient * WBC 14.5 * RBC 3.73 * Platelets 302 * HGB 10.0 * HCT 30.0 * Neutrophils 76 * Lymphocytes 16 * Monocytes 8 * Eosinophils 0 * Basophils 0 Reference 4.8 - 10.8 K/uL 4.6 - 6.1 M/uL 145 - 400 K/uL 14.0 - 18.0 g/dL 40.0 - 52.0 % 40 - 74 % 15 - 47 % 0 - 12 % 0-6 % 0-2 % CASE STUDY (20 M) – CMP (DAY 2) * * * * Glucose Protein(T) Albumin AST Patient 129 5.2 2.3 2.0 Reference 72 - 112 mg/dL 6.1 - 8.0 g/dL 3.5 - 4.8 g/dL 15 - 37 U/L All other analytes within reference ranges CASE STUDY (20 M) – CSF STUDIES (DAY 3) * * * * * * * Glucose Protein WBC RBC Neutrophils Lymphocytes Monocytes * Bacterial antigens Patient 34 100 576 14 42 28 30 Negative Reference 40 - 70 mg/dL 15 - 45 mg/dL uL uL % % % Negative CASE STUDY (20 M) – CSF CULTURE AND SMEAR (DAY 3) * Routine * 0 to 1 WBC/HPF * No organisms seen on gram stained smear * Acid-fast bacilli * No acid fast bacilli seen on fluorochrome stained smear * Fungus * No fungal elements seen on PAS stained smear CASE STUDY (20 M) – MOLECULAR MICROBIOLOGY (DAY 3) * Cerebrospinal fluid (CSF) by PCR * HSV-1 and HSV-2 DNA * Enterovirus RNA * Borrelia burgdorferi DNA Negative Negative Negative CASE STUDY (20 M) – MICROBIOLOGY AT NHRMC (DAY 3) * Ear drainage growth * Pseudomonas aeruginosa * Blood cultures * Negative at day 3 and day 5 * Cerebrospinal fluid cultures * Negative CASE STUDY (20 M) – BLOOD CULTURES (SRMC-DAY 3) * Streptococcus pneumoniae * * * * * * * * Penicillin G Ceftriaxone Azithromycin Trim/Sulfa Chloramphenicol Moxifloxacin Tetracycline Vancomycin Resistant Resistant Resistant Resistant Susceptible Susceptible Susceptible Susceptible CASE STUDY (20 M) IMMUNOLOGY (DAY 3) * Consultation between infectious disease and clinical microbiology * * * * * * Monospot test RPR Antinuclear antibody (ANA) Complement (T) HIV-1/2 antibody Serum protein electrophoresis (SPE) CASE STUDY (20 M) IMMUNOLOGY (DAY 3) * Monospot test Negative * RPR Negative * Antinuclear antibody (ANA) Negative * Complement (T) 48 U/mL * HIV-1/2 antibody Invalid * Serum protein electrophoresis Severe hypogammaglobulinemia [31 – 66 U/mL] PRINCIPLES OF HIV-1/2 ANTIBODY TEST * Lateral flow immunochromatographic procedure * Antigens and antibody immobilized onto nitrocellulose membrane in T and C zones * Test (T) Zone * Synthetic peptides from HIV envelope region * Control (C) Zone * Goat anti-human IgG * Developer solution * Facilitates flow of specimen onto test strip * Rehydrates protein-A gold colorimetric reagent CASE STUDY (20 M) – IMMUNOLOGY (DAY 4) Patient Reference * Immunoglobulin A (IgA) < 15.0 81 - 463 mg/dL * Immunoglobulin G (IgG) < 60.0 694 - 1618 mg/dL * Immunoglobulin M (IgM) < 5.0 48 - 271 mg/dL CASE STUDY (20 M) – DIFFERENTIAL DIAGNOSIS * Bruton’s X-linked agammaglobulinemia (XLA) * Common variable immunodeficiency (CVID) * Severe combined immunodeficiency (SCID) * Omenn syndrome (OS) CASE STUDY (20 M) - MOLECULAR PATHOLOGY (FLOW CYTOMETRY) * * * * * CD3+/CD5+ CD4 lymphocytes CD8 lymphocytes CD19+/CD20+ CD3-/CD56+ Patient Reference 79% 45% 30% 18% 3% 52 – 84% 30 – 61% 12 – 42% 5 – 25% 5 – 30% CASE STUDY (20 M) – FLOW CYTOMETRY Percent * Lymphs (CD45) * T-Lymphs (CD3) * % T-Lymphs (CD3/CD45) 1175 687 45 Reference 1000 - 4800 690 – 2540 55 – 84 76 * T-Helper lymphs (CD3+CD4) * %T-Helper lymphs (CD3+CD4/CD45) Cells/uL 1540 410 – 1590 31 – 60 CASE STUDY (20 M) – CLINICAL MANIFESTATION (DAY 5) * Herpetiform vesicles on erythematous base * Side of head * Lower lip * External ear * CN V3 herpes zoster reactivation CASE STUDY (20 M) – DISCHARGE DIAGNOSES (DAY 5) * Pneumococcal meningitis with bacteremia * Pseudomonas aeruginosa otitis externa * Common variable immunodeficiency (CVID) * CN V3 herpes zoster reactivation COMMON VARIABLE IMMUNODEFICIENCY (CVID) * Most prevalent primary immunodeficiency * Heterogeneous group of immunologic disorders * Unknown etiology * Characterized by marked deficiency of * IgG and IgA * IgM and T-cell dysfunction * Generalized lymphadenopathy and splenomegaly CVID – PATHOPHYSIOLOGY * Number of mechanisms for defective antibody production * B-cell defects * Differentiation of B-cells into plasma cells * T-cell defects * Low level expression of CD40 ligand CVID – EPIDEMIOLOGY * Prevalence of 1 case in 10,000 to 50,000 population * Female to male ratio of 1 * All races * Age at diagnosis * 1 to 5 years * 16 to 20 years * 21 years and greater (60%) CVID – COMPLICATIONS AND RISKS * Recurrent infections * Upper and lower respiratory tract * Streptococcus pneumoniae and Haemophilus influenzae * Herpes labialis (HSV) * Herpes zoster (VCV) * Autoimmune diseases (RA, AHA, ATP) * Malignancy * Non-Hodgkin’s lymphoma * Malignant lymphoma